JP2007524619A - Fluvastatin sodium crystalline form, process for its preparation, composition containing it, and use thereof - Google Patents

Abstract

Provided are processes for the preparation of fluvastatin sodium in amorphous form.

Description

  The present invention relates to fluvastatin, an antihypercholesterolemic and antilipidemic agent, and more particularly to its solid state monosodium salt.

  Complications of cardiovascular disease (eg, myocardial infarction, stroke, and peripheral vascular disease) account for half of deaths in the United States. High levels of low density lipoprotein (LDL) in the bloodstream can interfere with and destroy the bloodstream and are associated with coronary artery lesions that promote thrombus. Goodman and Gilman, “The Pharmacological Basis of Therapeutics”, 879 (9th edition, 1996). Lowering plasma LDL levels has been shown to reduce the risk of clinical symptoms in patients with cardiovascular disease and patients without cardiovascular disease but with hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.

  Statin drugs are currently the most therapeutically effective drugs available to reduce LDL levels in the bloodstream of patients at risk for cardiovascular disease. This class of drugs includes, inter alia, compactin, lovastatin, simvastatin, pravastatin, and fluvastatin. The mechanism of action of statin drugs has been elucidated in some detail. They disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid, which is the rate-limiting step in cholesterol biosynthesis. The inhibition thus reduces the rate of cholesterol production in the liver.

[R ^* , S ^* -(E)]-(±) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -3,5- Dihydroxy-6-heptenoic acid is a statin drug. This is known by the common name fluvastatin and has the molecular formula (I) described in the form of the free acid:

Fluvastatin is commercially available under the trade name Lescol®. Fluvastatin is provided as a monosodium salt in capsules containing 20-40 mg fluvastatin and as a long-release tablet containing 80 mg fluvastatin. Fluvastatin and its sodium salt are described in US Pat. No. 4,739,073. In Example 6 (a) of the '073 patent, the methyl ester precursor of (±) fluvastatin was hydrolyzed with sodium hydroxide in methanol, which was taken up in water, lyophilized after evaporation of methanol. . The lyophilized product had a melting point range of 194-197 ° C. In Example 8, the sodium salt was prepared by ring opening of fluvastatin lactone with sodium hydroxide in ethanol as described in Example 6 (b). The product of Example 8 gave infrared spectra in KBr pellets with bands at 3413, 2978, 2936, 1572 and 1216 cm ⁻¹ .

In US Pat. No. 6,124,340, lyophilization of fluvastatin sodium, as performed in Examples 6 (b) and 8 of the '73 patent, was performed in crystalline form (described as Form A) and amorphous material. Solid fluvastatin sodium as a mixture of The '340 patent gives the spectroscopic properties of another crystalline form of fluvastatin sodium which is said to be less hygroscopic and light stable. The other type is called Form B in the '340 patent. This is characterized by an infrared spectrum having bands at 3343, 2995, 1587, 1536, 1386, 1337, 1042 and 1014 cm ⁻¹ and the following powder X-ray diffraction peak positions and intensities.

  Fluvastatin sodium form A is said to have the following X-ray diffraction peak positions and intensities.

  US Patent Application 2003/0032666 reports the presence of four crystalline forms of fluvastatin monosodium salt (referred to as C, D, E and F forms). The moisture content of these types ranges from 3 to 32%. A new crystalline form of fluvastatin sodium was obtained by storing the sample in an atmosphere with a relative humidity range of 20-90%.

  In the '666 publication, the PXRD pattern of fluvastatin sodium type C has characteristic peaks with the following d values and qualitative intensity.

Where (vs) = very strong intensity; (s) = strong intensity; (m) medium intensity; (w) = weak intensity; and (vw) = very weak intensity.

  In the '666 publication, the PXRD pattern of fluvastatin sodium D type has characteristic peaks with the following d values and qualitative intensity.

  In the '666 publication, the fluvastatin sodium type E PXRD pattern has characteristic peaks with the following d values and qualitative intensities.

  In the '666 publication, the PXRD pattern of fluvastatin sodium form F has characteristic peaks with the following d values and qualitative intensity.

  International Patent Publication WO 02/36563 discloses crystal forms of enantiomerically pure [3R, 5S] and [3S, 5R] fluvastatin sodium.

  The invention also relates to fluvastatin sodium and the properties it exhibits in the condensed phase. The presence of different crystal forms (polymorphism) is a property of certain molecules and molecular complexes. Single molecules such as fluvastatin of formula (I) or salt complexes such as fluvastatin sodium have various physical properties such as melting points, X-ray diffraction patterns, infrared absorption fingerprints, and NMR spectra Give a solid. Crystal forms give different thermal behavior than amorphous materials or other crystal forms. Thermal behavior is measured in the laboratory by methods such as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), and is used to distinguish one polymorph from another. be able to. Differences in physical properties between different crystal types are caused by the orientation of adjacent molecules (complexes) in the bulk solid and intermolecular interactions. Thus, a polymorph is a characteristic solid with the same molecular formula but with advantageous and / or disadvantageous physical properties compared to other types in the polymorph family. These properties are affected by controlling the conditions under which the salt is obtained as a solid.

  An example of physical properties in the solid state is the fluidity of the ground solid. Flowability affects the ease with which the material can be handled during processing into a drug. When the particles of the powdered compound cannot easily pass through each other, the formulation specialist should take this fact into account in the development of tablet or capsule formation, which includes colloidal silicon dioxide, talc, starch, or tricalcium phosphate It may require the use of such a direct hitting lubricant.

  One of the most important physical properties of a pharmaceutical polymorphism is its solubility in aqueous solutions, especially in the patient's gastric fluid. For example, if absorption in the gastrointestinal tract is slow, drugs that are unstable to the conditions of the patient's stomach or small intestine are preferably slow to dissolve so that they do not accumulate in harmful environments. On the other hand, this method is not effective when the efficacy of the drug correlates with the peak of the blood flow level of the drug, such as a statin drug. For statin drugs, the more rapidly dissolved form will be more effective than the equivalent amount of the more slowly dissolved form if absorbed rapidly by the GI system.

  The most rapidly dissolving solid state of a compound is often amorphous. The amorphous type is more unstable than the crystalline type because there are not many intermolecular interactions having a stabilizing action that exist in the crystalline type. Therefore, in the amorphous type, it is not necessary to destroy the intermolecular interaction having a stabilizing action when the compound enters the solution, and thus the dissolution rate is not slowed down. Amorphous compounds dissolve faster than crystalline forms, but these have drawbacks. When a compound is in an amorphous state, it is often more hygroscopic than the crystalline form of the same compound (e.g., a crystal has a wide channel that allows water to enter and exit in response to changes in moisture density outside the crystal. There are many exceptions, like if you have). Water is said to be involved in drug stability issues. For example, the degradation of aspirin is a water-catalyzed hydrolysis reaction so that when a bottle of aspirin is opened, it has a characteristic vinegar smell. Therefore, when choosing a solid state form of a compound that is used as a drug and possibly stored for long periods between packaging and use, it is advisable to choose a form with low water permeability. In the case of fluvastatin monosodium, the crystalline form of the salt obtained by the following method of US Pat. Has been discovered.

  Six distinct crystal forms of racemic fluvastatin sodium have been reported to date, and at least one of them is said to be less hygroscopic than the solid state form originally reported by compound discovery However, the discovery of yet another crystalline form of fluvastatin sodium is preferred. The discovery of new crystal forms and solvates of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of drug products by expanding the repertoire of materials available to pharmaceutical scientists. For example, designing drug dosage forms with low hygroscopicity, targeted release profile, constant dosage (allowed by good flow of the tableting composition into the tableting die), or other desired properties However, new crystal forms can be used. Currently, new types and solvates of fluvastatin have been discovered.

  In certain embodiments, the present invention provides various polymorphisms of fluvastatin sodium. Polymorphisms are particularly identified by various characteristic PXRD peaks.

  In another aspect, the present invention provides a method for preparing these polymorphisms. These polymorphs are prepared by the various methods described in the examples and the detailed description of the invention.

  In another aspect, the present invention provides agents prepared from such polymorphisms.

  In another aspect, the present invention provides a method for treating hypercholesterolemia or hyperlipidemia in a mammal by administering a pharmaceutical composition to the mammal.

  These polymorphs are particularly the starting point for the preparation of a pharmaceutical composition of fluvastatin sodium (since many are crystalline), for the purification of fluvastatin and / or for the preparation of other polymorphs of fluvastatin sodium. Useful as a substance.

  The claims further provide a summary of the invention. Although the claims are not in many dependency formats, the summary of the present invention includes claims that depend on all possible product claims, ie the same polymorphism, and methods described in all other possible method claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, a lower alkyl group means a C1-C4 alkyl group.
The present invention relates to [R ^* , S ^* -(E)]-(±) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl]- A new crystalline form of 3,5-dihydroxy-6-heptenoic acid monosodium salt (fluvastatin sodium) is provided. The new crystal forms of fluvastatin sodium are I, II, III, IV, IV-1, V, VI, VII, XI, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX , XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII , XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, and CV types. Thus we choose to use Roman numerals instead of the Roman alphabet used by other researchers in this field to name other crystal forms of fluvastatin sodium.

  Fluvastatin sodium crystal forms XIV, LXXIII, LXXIX, LXXX and LXXXVII appear in the priority application of the present invention and are present in another application on the same day.

Whether the two enantiomers of [R ^* , S ^* -(E)]-(±) fluvastatin sodium co-crystallize in a single unit cell, or in another unit cell where they are mirror images of each other Whether or not to crystallize has not yet been determined for all new crystal types. Thus, the crystalline forms of the present invention are those that are pure or concentrated [R ^* , S ^* -(E)]-(+) and [R ^* , S ^* -(E)]-(−) fluvastatin sodium Or starting from racemic fluvastatin sodium shows substantially the same PXRD pattern as shown in the figure.

  Many of the new molds can be obtained by crystallization methods and are stable under normal humidity conditions. Those of skill in the art will understand after reading this disclosure that some of the crystallization methods that created this new mold share some properties. In general, in these methods, fluvastatin sodium can be dissolved in a solvent whose choice is taught for each particular crystal form in the columns of this disclosure below. When the solution of fluvastatin sodium in the solvent is refluxing, the selected anti-solvent (the choice is taught below) is added to the solution to induce precipitation of fluvastatin sodium in the desired crystalline form. It is done. It is preferred that the anti-solvent addition and precipitation be performed, or performed at an elevated temperature. Of course, additional precipitation often occurs during the subsequent cooling of the mixture. It will also be appreciated that in other methods, heating the solvent is not preferred.

  By the crystallization method of the present invention, each new crystalline form of fluvastatin sodium can be obtained substantially free of other crystalline forms, which is less than 5% of other crystalline forms as measured by X-ray powder diffraction It means that. While these methods give new crystal forms and are known to give them in high purity, no other methods have been found to produce the crystal forms of the present invention with higher or lower purity.

  The yield of the various methods for preparing a new fluvastatin sodium crystal form varies greatly depending on the desired form. One skilled in the art will appreciate that the low yield of the desired crystal form does not necessarily mean that valuable unconverted starting material is lost. For example, by evaporating the separated diluent or solvent used in the process to leave a residue containing fluvastatin, it is removed from the separated solvent or diluent, or other crystalline or amorphous Forms of fluvastatin sodium or fluvastatin free acid or lactone can be recovered.

  Some of the newer forms of fluvastatin sodium are hydrated. The level of water in fluvastatin sodium is measured by the Karl Fischer method using methods known in the art. Some of the new crystalline forms of fluvastatin sodium contain residual solvent in addition to water, which is understood by the fact that the TGA weight loss value is significantly greater than the Karl Fischer value. Some of the solvated crystal forms contain only a small amount of residual solvent. In this latter group, fluvastatin sodium is in the following hydrated state: hemihydrate (water content about 2%); monohydrate (water content about 3-4%); sesquihydrate (water content) Dihydrate (water content about 7-8%); hemipentahydrate (water content about 9-10%); trihydrate (water content about 11-13%); Hydrate (water content about 14-16%); pentahydrate (water content about 17-18%); hexahydrate (water content about 19-20%); octahydrate (water content about 25%) %); Nonahydrate (water content about 27-28%).

  Fluvastatin is commercially available or can be synthesized by known methods such as those disclosed in US Pat. No. 4,739,073, which is hereby incorporated by reference in its entirety. A compound. In particular, US Pat. No. 4,739,073 is incorporated herein by reference with particular reference to the disclosure of methods for preparing fluvastatin and fluvastatin sodium. In the method of the present invention using fluvastatin sodium as a starting material, fluvastatin sodium Form B is a preferred starting material unless otherwise specified.

  The term “high temperature” as used in this disclosure means ambient temperature or a temperature greater than about 25 ° C. A suitable high temperature is 50 ° C. and above, and when used for contact with certain liquids, a particularly preferred high temperature is the boiling point of such liquids.

  The term “antisolvent” means a liquid that induces precipitation of fluvastatin sodium when added to a solution of fluvastatin in a solvent. The addition of antisolvent is more rapid than when fluvastatin sodium precipitates from a solution containing the same concentration of fluvastatin in the same solvent when the solution is maintained for the same time under the same conditions but without the antisolvent. Fluvastatin sodium precipitation is induced by an antisolvent when it causes precipitation of fluvastatin sodium from the solution to a greater or lesser extent. Precipitation is visually recognized by the cloudiness of the solution or the formation of distinct particles of fluvastatin sodium collected at the surface of the suspended or solution or at the wall or bottom of the container containing the solution.

Fluvastatin sodium crystalline Form I Fluvastatin sodium Form I gives a PXRD diffractogram with 3.7, 111.3, 13.1, 17.9, 18.4 and 21.8 degrees (2θ) (Figure 1).
Fluvastatin sodium Form I can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. This ester is conveniently provided by dissolving an appropriate amount of sodium hydroxide pellets in water, acetone, or acetonitrile, taking care that dissolution in water is highly exothermic. Fluvastatin sodium Form I is formed as a precipitate in a solvent and can be conveniently separated therefrom by known isolation methods such as filtration, decanting, centrifugation, etc., preferably by filtration under a stream of nitrogen.

  Form I can also be prepared by crystallization from a mixture of acetone or butan-2-ol and water, with a 10: 1 butan-2-ol and water mixture being particularly preferred. Preferably, Form B is dissolved in the solvent at the reflux temperature of the solvent by adding Form B to the refluxing solvent.

  In a preferred method, about 0.05: 1 (w / v) Form B is added to refluxing acetone. If Form B does not completely dissolve after a suitable time, the hot solution may be filtered to remove undissolved particles. Then about 1: 3 (v / v) MTBE is added to the solution. The mixture is then allowed to cool. If Form I does not precipitate after cooling to ambient temperature, an additional amount of MTBE can be added to the solution and it can be partially concentrated on a rotary evaporator to induce precipitation. The product is then isolated using conventional methods.

  In another preferred method, about 1:20 (w / v) Form B is added to the refluxing 10: 1 butan-2-ol: water mixture. After complete dissolution, the mixture is cooled or allowed to cool to induce precipitation and form I is conveniently isolated.

Fluvastatin Sodium Crystalline Form II Fluvastatin Sodium Form II has a characteristic peak at 3.6 ± 0.2 degrees (2θ) and PXRD diffraction with other peaks at 5.4, 5.7, 10.7 and 20.3 ± 0.2 degrees (2θ) (Figure 2) Give.

  Form II can be prepared from fluvastatin sodium such as Form B or amorphous fluvastatin. Starting from Form B, the starting material is taken up in refluxing butan-1-ol. The solution is then cooled or left to cool to ambient temperature and left without seeding until a precipitate is observed. Starting with amorphous fluvastatin sodium, about 1:21 (w / v) of starting material is suspended in refluxing propan-2-ol. The suspension is then cooled and allowed to settle until precipitation occurs.

  After either method, the precipitate is separated from the diluent by conventional methods (eg, filtration, decanting, centrifugation, etc.). Drying takes place in a vacuum oven at 50 ° C.

Fluvastatin sodium crystal form III Fluvastatin sodium crystal form III gives a PXRD diffractogram with 3.5, 9.5, 10.1, 10.9 and 20.1 degrees (2θ) (FIG. 3).

  Form III, like Form II, can be prepared from fluvastatin sodium form, such as Form B or amorphous fluvastatin. It can also be prepared from fluvastatin sodium crystal form XIV.

  Starting from Form B, the starting material is dissolved in a solvent selected from the group consisting of refluxing butan-1-ol, ethyl acetate, and THF. Form B is preferably dissolved at the reflux temperature of the solvent. If Form B is not completely dissolved, the hot solution can be filtered to obtain a clear filtrate. At reflux temperature, an antisolvent selected from the group consisting of MTBE, hexane, and cyclohexane is slowly added to the solution (dropwise on a bench scale). The addition of an antisolvent induces precipitation at high temperatures. If no precipitation is induced, Form III should precipitate when the solution is cooled to ambient temperature.

  Starting from amorphous fluvastatin sodium, about 1: 6 (w / v) of starting material is dissolved in refluxing ethanol. As the solution is refluxed, Form III should come out of solution. If this does not precipitate within about 1 hour, the solution can be cooled to ambient temperature to induce type III precipitation.

  Starting with fluvastatin sodium form XIV, about 1: 7 (w / v) of starting material is suspended in refluxing ethanol for a time sufficient to change to form III (this takes hours or days) . The suspension is then cooled to ambient temperature and the precipitate is isolated.

  In each of these methods for making fluvastatin sodium Form III, the product is separated from the dilution by conventional methods (eg, filtration, decanting, centrifugation, etc.). Drying takes place in a vacuum oven at 50 ° C.

Fluvastatin sodium crystal type IV fluvastatin sodium type IV has peaks characteristic of 3.6, 4.0, 9.8, 10.8, and 22.0 ± 0.2 degrees (2θ), and 6.5, 12.8, 16.3, 17.2, 18.3, 19.5, 20.6 and A PXRD diffractogram with an additional peak at 22.9 ± 0.2 degrees (2θ) is given (Figure 4). Fluvastatin sodium type IV gives the DSC thermogram shown in FIG. 5, where major endothermic peaks are seen below 70 ° C. and about 120 ° C. The moisture content of the sample measured with Karl Fischer is about 4% by weight. Weight loss by TGA is 8.3%. IR spectra of fluvastatin sodium type IV are shown in FIGS. 6, 6a and 6b.

  Fluvastatin sodium type IV dissolves fluvastatin sodium in refluxing tetrahydrofuran (“THF”) and organic poor solvents (eg, chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, and n-propane) into the refluxing solution. It can be prepared by adding dropwise. Form IV should precipitate from the refluxing mixture. The mixture is maintained at reflux temperature for the time necessary to achieve the desired yield of Form IV. The mixture can then be cooled to room temperature and Form IV can be isolated by known isolation methods such as filtration, decanting, centrifugation, and the like. Fluvastatin sodium Form IV is also the same method, but using butan-1-ol, 1,4-dioxane or propan-2-ol instead of THF, cyclohexane or methyl t-butyl ether (“MTBE”) Can be prepared as a poor solvent.

Fluvastatin Sodium Crystalline Form IV-1 Fluvastatin sodium Form IV has peaks characteristic of 3.6, 4.0, 9.6, 18.5, and 22.2 ± 0.2 degrees (2θ), and 6.6, 10.4, 11.0, 17.3, 19.5, PXRD diffractograms with additional peaks at 20.1, 20.7, and 21.3 ± 0.2 degrees (2θ) are given (FIG. 4). Fluvastatin sodium type IV-1 gives the DSC thermogram shown in FIG. 8, where major endothermic peaks are seen below 70 ° C. and about 120 ° C. The moisture content of the sample measured with Karl Fischer is about 2.1-2.6% by weight. The weight loss due to TGA is 10.5% by weight. IR spectra of fluvastatin sodium type IV-1 are shown in FIGS. 9, 9a and 9b.

  Fluvastatin sodium type IV-1 can be prepared by dissolving fluvastatin sodium in refluxing THF or 1,4-dioxane and adding n-heptane or MTBE dropwise. Fluvastatin sodium Form IV-1 can also be prepared by dissolving fluvastatin sodium in butan-2-ol and recrystallizing it during reflux.

Fluvastatin sodium crystal form V Fluvastatin sodium form V gives a PXRD diffractogram with characteristic peaks at 3.8, 6.3, 9.5, and 21.2 ± 0.2 degrees (2θ) (FIG. 10).

  To date, two methods for creating Form V have been discovered, both using fluvastatin B as the starting material. In one method, Form B is dissolved in refluxing butan-1-ol. After complete dissolution or filtration of the solution gives a clear solution, slowly add heptane to the reflux solution. The solution is then cooled and the precipitate is collected. In another method, Form B is dissolved at reflux temperature in a solvent system that is a 5: 2: 1 ternary mixture of ethanol: ethyl acetate: propan-1-ol. After complete dissolution or filtration of the solution gives a clear solution, slowly add n-hexane to the reflux solution. The solution is then cooled to ambient temperature and maintained until a precipitate forms. In either method, the product is separated from the diluent by conventional methods (eg, filtration, decanting, centrifugation, etc.). Drying takes place in a vacuum oven at 50 ° C.

Fluvastatin Sodium Crystalline Form VI Fluvastatin sodium Form VI has peaks characteristic of 3.7, 4.7, 5.7, 10.9, 12.2, and 19.9 ± 0.2 degrees (2θ) and 9.1, 14.3, 16.3, 16.9, 20.4, and 21.3 A PXRD diffractogram with an additional peak at ± 0.2 degrees (2θ) is given (Figure 11). Fluvastatin sodium type VI gives the DSC thermogram shown in FIG. 12, where major endothermic peaks are seen below 90 ° C. and about 130 ° C. The moisture content of the sample measured with Karl Fischer is about 5.0 to 5.6% by weight. The weight loss due to TGA is about 12% by weight. Fluvastatin sodium Form VI was stable after 12 days exposure to 0-40% RH relative humidity and equilibrated at a moisture content of 3-5%. At higher relative humidity this was converted to fluvastatin sodium type VII and D. IR spectra of fluvastatin sodium type VI are shown in FIGS. 13, 13a and 13b.

  Fluvastatin sodium Form VI can be prepared by dissolving fluvastatin sodium in DMF at room temperature and adding the organic poor solvent (eg, diethyl ether or hexane) dropwise to precipitate the material. Cool the mixture using an ice bath. Form VI can be separated from DMF and poor solvent by methods known in the art (for example, filtration, decantation, centrifugation, etc., preferably filtration under a nitrogen stream).

  Fluvastatin sodium Form VI can also be prepared directly from fluvastatin methyl ester. The starting material is dissolved in about 1 molar equivalent of sodium hydroxide solution in a solvent system selected from the group consisting of methanol, ethanol, a mixture of methanol and water, and a mixture of butan-1-ol and water. A preferred methanol: water mixture is 91% methanol, 9% water, and a preferred butan-1-ol: water mixture is 94% butan-1-ol, 6% water. The solvent system is preferably heated, for example to reflux temperature, to accelerate the conversion of the lactone to the sodium salt that may be present, and the process can be followed by HPLC. Once the starting material is completely dissolved, a poor solvent selected from the group consisting of acetonitrile and acetone is added dropwise to the solution at high temperature to induce precipitation. After cooling the mixture to ambient temperature, Form VI can be isolated by conventional methods (eg, filtration, decanting, centrifugation, etc.). Drying takes place in a vacuum oven at 50 ° C.

Fluvastatin Sodium Crystalline Form VII Fluvastatin sodium Form VII has characteristic peaks at 3.7, 4.3, 5.8, 8.6, and 20.7 ± 0.2 degrees (2θ), and 10.8, 12.3, 13.7, 15.8, 17.3, 19.4, 22.0, PXRD diffractograms with additional peaks at 23.9, 25.2, 26.2, and 27.6 degrees (2θ) are given (Figure 14). Fluvastatin sodium Form VII gives the DSC thermogram shown in FIG. 15, where major endothermic peaks are seen below 90 ° C. and about 130 ° C. The moisture content of the sample measured with Karl Fischer is about 4.1-4.5% by weight. Weight loss by TGA is 13-14% by weight. IR spectra of fluvastatin sodium type VII are shown in FIGS. 16, 16a and 16b.

  Fluvastatin sodium type VII was stable after 11 days exposure to 20-60% RH relative humidity and equilibrated at a moisture content of 1.4-8.6%. After exposure to 80% RH for 11 days, type VII is converted to a new type XX (water content: about 19%), and after exposure to 100% RH for 11 days, type VII is a new type XIV (water content: about 17%) Converted to The results are summarized in the following table.

  Dissolve fluvastatin sodium in N, N-dimethylformamide (“DMF”) at room temperature and add organic poor solvent (eg chloroform, MTBE, dichloromethane, cyclohexane, or 1,2-dichloroethane) dropwise to precipitate Can be prepared. An ice bath can be used to cool the mixture to enhance Type VII recovery. Form VII can be separated by methods known in the art (for example, filtration, decantation, centrifugation, etc., preferably filtration under a nitrogen stream).

  Fluvastatin sodium type VII also suspends fluvastatin sodium (preferably type B) in DMF at room temperature and uses methods known in the art such as filtration, decantation, centrifugation (preferably filtered under a stream of nitrogen), etc. Can be prepared.

  Another method of making fluvastatin sodium Form VII starts with a lower alkyl ester of fluvastatin. The starting material is dissolved in a solution containing about 1 molar equivalent of sodium hydroxide in a solvent selected from the group consisting of butan-1-ol, a mixture of water and propan-2-ol. A suitable mixture of water and propan-2-ol contains about 8% water and 92% propan-2-ol. The starting material is preferably dissolved at an elevated temperature, such as the reflux temperature of the solvent. Once a solution is obtained, an anti-solvent (acetone, acetonitrile, or MTBE) is added to the mixture at an elevated temperature to induce precipitation.

  Alternatively, the lower alkyl ester of fluvastatin is taken up in methanol at ambient or elevated temperature (preferably ambient temperature) to form a saturated solution. Saturated solutions can be prepared by producing an unsaturated solution and then evaporating the solvent until a solid or turbidity appears. The solution is then heated, preferably to the reflux temperature, until all solids are redissolved. In this manner, acetonitrile is then added dropwise to the solution to induce precipitation of fluvastatin sodium form VII.

  In yet another method starting from the lower alkyl ester of fluvastatin, the starting material is dissolved in acetonitrile. To effect dissolution, the acetonitrile is heated to 40 ° C. To this solution is then added a solution of sodium hydroxide in ethanol. The resulting mixture becomes turbid and the oil phase separates over time. When this happens, heat the mixture until the oil enters the solution. Form VII can then precipitate by cooling the solution or allowing it to cool.

  After allowing the mixture to cool to ambient temperature, Form VII can be isolated by conventional methods (eg, filtration, decanting, centrifugation, etc.). The liquid is preferably separated by vacuum filtration under an inert gas such as nitrogen. A suitable condition for drying the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline Form IX Fluvastatin sodium Form IX gives a PXRD diffractogram with characteristic peaks at 3.4, 10.0, and 19.7 ± 0.2 degrees (2θ) (FIG. 17).

  Form IX can be prepared by crystallization from various solvent systems according to the method detailed in the examples. Briefly, Form IX can be obtained by adding dichloromethane from a solution in 1,4-dioxane; by adding ethyl acetate, diethyl ether, or n-pentane from a solution in ethanol; or from a mixture of ethanol and methanol to hexane. It can be precipitated by addition. Furthermore, Form IX can be prepared by refluxing a suspension of Form B in ethyl acetate.

  Alternatively, Form IX can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. This ester is dissolved in a solution of about 1 molar equivalent of sodium in ethanol. Sodium is conveniently provided by dissolving an appropriate amount of sodium hydroxide pellets in water, taking care that dissolution in water is highly exothermic. This solution is heated for a time sufficient to hydrolyze the ester, typically several hours. Then a large amount (eg 7 × v / v) of propan-2-ol is added to this solution. The mixture is then cooled to room temperature and maintained until a precipitate forms in the flask.

  Form IX is conveniently separated by known isolation methods such as filtration, decanting, centrifugation, etc., preferably by filtration under a stream of nitrogen.

Fluvastatin sodium crystal form IX-1 Fluvastatin sodium form IX-1 gives a PXRD diffractogram with characteristic peaks at 3.4, 6.6, 10.0, 13.2, 19.8 ± 0.2 degrees (2θ) (FIG. 18).

  We have found a number of ways to make type IX-1, which are exemplified by starting from fluvastatin type B. For simplicity, see the examples for details of its creation.

Fluvastatin Sodium Crystalline Form XI Fluvastatin sodium Form XI has characteristic peaks at 3.3, 3.8, 4.6, 8.3, 10.2 and 25.1 ± 0.2 degrees (2θ) and 7.2, 11.4, 12.4, 13.6, 16.0, 16.9, 17.4 PXRD diffractograms with additional peaks at 20.4, 21.3, 21.9, and 23.1 ± 0.2 degrees (2θ) are given (FIG. 19). Fluvastatin sodium Form XI gives the DSC thermogram shown in FIG. 20, where a major endothermic peak is seen at about 150 ° C. The water content of the sample is about 4-6% by weight. The weight loss due to TGA is 6-8% by weight. IR spectra of fluvastatin sodium form XI are shown in FIGS. 21, 21a and 21b.

  Fluvastatin sodium form XI was stable after 11 days exposure to 20-60% RH relative humidity and equilibrated at 1.1-5.6% moisture content. After 11 days exposure to 80% RH and 100% RH, form XI was converted to a new form XIX (water content: about 19-28%). The results are summarized in the following table.

  Fluvastatin sodium form XI can be prepared by dissolving fluvastatin sodium, preferably form B, in refluxing butan-2-ol. During reflux, fluvastatin sodium recrystallizes in Form XI. The addition of an organic antisolvent (eg, hexane, n-pentane, MTBE, diethyl ether, n-heptane, and chloroform) during reflux tends to increase the yield of the precipitate. The mixture is maintained at reflux temperature for the time necessary to achieve the desired yield of Form XI. The mixture is then cooled to room temperature and Form XI can be separated by isolation methods known in the art (eg, filtration, decanting, centrifugation, etc., preferably filtration under a stream of nitrogen).

Fluvastatin Sodium Crystalline Form XI-2 Fluvastatin sodium Form XI-2 has peaks characteristic of 3.5, 3.8, 4.6, 10.4, and 18.5 ± 0.2 degrees (2θ), 8.5, 11.2, 12.1, 16.4, 17.0, PXRD diffractograms with additional peaks at 17.7, 20.9, 21.2, 21.7, 22.2, and 23.6 ± 0.2 degrees (2θ) are given (FIG. 22). Fluvastatin sodium form XI-2 gives the DSC thermogram shown in FIG. 23, where major endothermic peaks are seen below 80 ° C. and about 145 ° C. The moisture content of the sample is about 1.9-3.2% by weight. The weight loss due to TGA is 7.7% by weight. Fluvastatin sodium form XI-2 was stable after 11 days exposure to 0-60% RH relative humidity and equilibrated at 5-7% moisture content. At higher relative humidity, this was converted to type D. IR spectra of fluvastatin sodium form XI-2 are shown in FIGS. 24, 24a, and 24b.

  Fluvastatin sodium form XI-2 can be prepared by dissolving fluvastatin sodium in refluxing propan-1-ol and adding an organic poor solvent (eg, hexane, MTBE and dichloromethane) dropwise. The mixture is maintained at reflux temperature for the time necessary to achieve the desired yield of Form XI-2. The mixture is then cooled to room temperature and Form XI-2 can be separated by known isolation methods (eg filtration, decanting, centrifugation, etc., preferably filtration under a stream of nitrogen).

Fluvastatin sodium crystalline form XII Fluvastatin sodium form XII gives PXRD diffractograms with characteristic peaks at 3.1, 6.5, 9.8, 17.6, 25.9, and 30.9 ± 0.2 degrees (2θ) (FIG. 25).

  Form XII is prepared by crystallization from a mixture of butan-1-ol and 1,4-dioxane. In a preferred method, Form B is dissolved in refluxing butan-1-ol. Then 1,4-dioxane is added here until the reflux solution becomes cloudy. The mixture is then cooled to ambient temperature where additional 1,4-dioxane is added to increase Form XII recovery. Type XII can be separated from the solvent system by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated form XII is dried. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin sodium crystalline Form XIII Fluvastatin sodium Form XIII gives a PXRD diffractogram with characteristic peaks at 3.8, 5.6, 12.3, and 20.6 ± 0.2 degrees (2θ) (FIG. 26).

  Form XIII can be prepared by suspending fluvastatin sodium Form B in acetonitrile (which is preferably done at an elevated temperature) and then cooling the suspension to a lower temperature (eg 10 ° C.). Form XIII can be separated from acetonitrile by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated form XIII is dried. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline XV Israel in response to a commercial order issued to Zhejiang Hisun Pharmaceutical Co., Ltd. (46 Waisha Rd., Jiaojiang District, Taizhou City, Zhejiange Province, China) This material received in XXRD was subjected to PXRD analysis at our facility in Israel, resulting in the PXRD diffractogram shown in FIG. 30, which is the other solid state form of fluvastatin sodium disclosed herein. Each diffraction pattern is clearly different. We designed this solid state form of fluvastatin sodium form XV. Form XV has been found to be useful in preparing several new solid state forms of fluvastatin sodium as described below.

Fluvastatin sodium crystal form XVI Fluvastatin sodium crystal form XVI has characteristic peaks at 3.8 and 7.0 ± 0.2 degrees (2θ), 4.3, 10.2, 10.7, 11.2, 15.6, 17.8, 18.4, and 19.5 ± 0.2 degrees ( A PXRD diffractogram with another peak at 2θ) is given (Figure 31). Fluvastatin sodium XVI gives the DSC thermogram shown in FIG. 32, where a broad endothermic peak is seen below 80 ° C. and about 100-150 ° C. The water content of the sample is about 3-4% by weight. The weight loss due to TGA is 8.7% by weight. IR spectra of fluvastatin sodium form XVI are shown in FIGS. 33, 33a, and 33b.

  Fluvastatin sodium form XVI can be prepared by dissolving fluvastatin sodium in refluxing propan-2-ol and adding dropwise an organic poor solvent (eg dichloromethane) dropwise. The mixture is maintained at reflux temperature for the time necessary to achieve the desired yield of Form XVI. The mixture is then cooled to room temperature and Form XVI can be isolated by known isolation methods (eg, filtration, decanting, centrifugation, etc.).

Fluvastatin sodium crystal form XVII Fluvastatin sodium crystal form XVII has peaks characteristic of 3.5 (broad), 5.4, 5.8, and 13.8 ± 0.2 degrees (2θ), and 10.8, 14.8, 16.4, 19.4, 21.5, and 22.7 A PXRD diffractogram with another peak at ± 0.2 degrees (2θ) is given (Figure 34). Fluvastatin sodium form XVII gives the DSC thermogram shown in FIG. 35, where broad endothermic peaks are seen below 80 ° C. and about 113 ° C., respectively. The weight loss due to TGA is 8.4% by weight.

  Fluvastatin sodium Form XVII can be prepared by dissolving fluvastatin sodium in refluxing propan-1-ol and recrystallizing it from a stirred solution. In a preferred embodiment, recrystallization is performed at an elevated temperature.

Fluvastatin sodium crystal form XVIII Fluvastatin sodium crystal form XVIII has peaks characteristic of 3.4, 8.4, 10.0, and 10.9 ± 0.2 degrees (2θ), and 11.7, 12.6, 15.8, 17.4, 18.0, 18.8, 20.0, 20.7 And a PXRD diffractogram with other peaks at 21.3 ± 0.2 degrees (2θ) (FIG. 36). Fluvastatin sodium form XVIII gives the DSC thermogram shown in FIG. 37, where broad endothermic peaks are seen below 70 ° C. and about 180 ° C. The water content of the sample is about 4% by weight. In TGA, the decrease due to drying is about 4% by weight. Fluvastatin sodium form XVIII is a monohydrate. IR spectra of fluvastatin sodium form XVIII are shown in FIGS. 38, 38a, and 38b.

  Fluvastatin sodium form XVIII can be prepared by suspending fluvastatin sodium in refluxing methyl ethyl ketone (MEK). The mixture is maintained at the reflux temperature for the time necessary to achieve the desired yield of Form XVIII. The mixture is then cooled to room temperature and Form XVIII can be isolated by known isolation methods (eg filtration, decanting, centrifuging, preferably filtration or distillation under a stream of nitrogen).

Fluvastatin sodium crystalline form XIX Fluvastatin sodium form XIX has characteristic peaks at 3.4, 10.1, 13.5, and 18.0 ± 0.2 degrees (2θ), and other peaks at 6.8, 20.1, 21.8, and 25.6 ± 0.2 degrees (2θ) A PXRD diffractogram with a peak of is given (Figure 39). Fluvastatin sodium Form XIX gives the DSC thermogram shown in Figure 40, where one major endothermic peak is seen at about 80 ° C. The water content of the sample is 19-28% by weight. The weight loss by TGA is about 22-26% by weight. Fluvastatin sodium form XIX is a hexahydrate, octahydrate, and nonahydrate form. IR spectra of fluvastatin sodium form XIX are shown in FIGS. 41, 41a, and 41b.

  Fluvastatin sodium form XIX can be prepared by exposing form XI, form IV-1 or form XVI to a high humidity atmosphere ranging from about 60% to about 100% RH.

Fluvastatin sodium crystal form XIX-1 Fluvastatin sodium form XIX-1 has characteristic peaks at 3.5, 10.4, 11.9, 14.0, and 22.5 ± 0.2 degrees (2θ), and 17.5, 17.8, 18.0, 18.3, 25.4 ± A PXRD diffractogram with another peak at 0.2 degrees (2θ) is given (Figure 42). The water content of fluvastatin sodium XIX-1 measured by Karl Fischer is about 8% by weight. The weight loss due to TGA is about 7% by weight. Fluvastatin sodium form XIV is a dihydrate.

  Fluvastatin sodium form XIX-1 is prepared by forming a heterogeneous mixture of fluvastatin sodium form XI and water and maintaining this mixture for a time sufficient to achieve the desired yield of form XIX-1. can do. This mixture is stirred, preferably from about 2 hours to about 15 hours, with about 5 hours being particularly preferred. The product is then recovered from the mixture by conventional methods (eg filtration).

  The recovered wet product is then dried from time to time. The drying is processed at a suitable temperature range of about 40 ° C. to about 60 ° C. for about 12 hours to about 48 hours.

Fluvastatin sodium crystal form XX Fluvastatin sodium form XX has PXRD with characteristic peaks at 3.5, 10.1, 13.5, 18.0 and 20.8 ± 0.2 degrees (2θ) and other peaks at 5.9 and 12.4 degrees (2θ) A diffractogram is given (Figure 43). Fluvastatin sodium form XX gives the DSC thermogram shown in Figure 44, where one major endothermic peak is seen below about 130 ° C. The water content of the sample is 19% by weight. In TGA, the decrease due to drying is about 19% by weight. Fluvastatin sodium form XX is a hexahydrate. IR spectra of fluvastatin sodium form XX are shown in FIGS. 45, 45a, and 45b.

  Fluvastatin sodium form XX can be prepared by exposing form VII to an atmosphere with a relative humidity of about 80% or more for a time sufficient to effect the change of form XX.

  In the case of fluvastatin sodium XI, XIV, XVIII, XIX, and XX, TGA and Karl Fischer analysis are almost consistent, indicating that these samples are predominantly hydrated.

  For fluvastatin sodium types IV, IV-1, VI, VII and XI-2, the TGA analysis is larger than the Karl Fischer analysis, which is thought to indicate the presence of a substantial amount of organic solvent. After 11 days of exposure to 60% relative humidity, the difference in TGA and KF results was smaller (see types VII and XI stored at different relative humidity), indicating a decrease in organic solvent levels. Consequently, exposure to humidity is a useful way to reduce the organic solvent present in fluvastatin sodium.

Fluvastatin sodium crystal form XXII Fluvastatin sodium form XXII has characteristic peaks at 3.2, 12.4, and 18.3 ± 0.2 degrees (2θ) and other peaks at 6.4, 9.5, 15.6, and 21.4 degrees (2θ) A PXRD diffractogram is provided (Figure 46).

  Form XXII can be prepared by exposing fluvastatin sodium form XV to water vapor. Preferably type XV is maintained at ambient temperature in an atmosphere of 100% relative humidity. Substantially complete conversion is achieved in a few weeks, typically about 2 weeks.

Fluvastatin sodium crystal form XXIII Fluvastatin sodium form XXIII has peaks characteristic of 3.6, 4.0, 4.4, 17.1, and 19.3 ± 0.2 degrees (2θ), and 6.2, 7.2, 9.3, 10.2, and 18.6 degrees (2θ) Gives a PXRD diffractogram with other peaks (FIG. 47).

  Form XXIII can be prepared by dissolving about 1:20 (w / v) fluvastatin sodium Form B in refluxing propan-1-ol. Several hours after complete dissolution, fluvastatin sodium begins to precipitate in XXIII. After initial crystal formation, the mixture is cooled or allowed to cool to ambient temperature and fully crystallize to obtain Form XXIII. Form XXIII can be separated from propan-1-ol by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated form XXIII is dried. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Form XXIV Fluvastatin sodium Form XXIV has peaks characteristic of 3.4, 10.2, 13.6, 17.9, and 18.7 ± 0.2 degrees (2θ), and 6.9, 10.7, 12.0, 22.5, and 25.4 degrees (2θ) A PXRD diffractogram with other peaks is given (Figure 48).

  Form XXIV can be prepared from fluvastatin sodium form B and fluvastatin form XV. XXIV is obtained by crystallizing these forms from water. When starting from Form XV, the starting material is dissolved in refluxing water. After hours to days of cooling the solution to ambient temperature, Form XXIV crystallizes from the solution. Form XXIV can be separated from water by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated form XXIV is dried. A suitable drying condition is 50 ° C. under vacuum. When starting from Form B, the starting material can be dissolved in water at ambient temperature. If type XXIV does not crystallize, the method can be modified as follows. Diethyl ether is added to the container containing the solution and allowed to contact the solution for several minutes. The phases are then separated and the aqueous phase is lyophilized to give a residue that is fluvastatin sodium form XXIV.

Fluvastatin sodium crystal form XXVI Fluvastatin sodium form XXIV has characteristic peaks at 3.8, 15.0, 18.5, 21.6, and 25.8 ± 0.2 degrees (2θ), and 11.7, 15.9, 16.2, 24.3, and 35.2 degrees (2θ) Gives a PXRD diffractogram with other peaks (FIG. 49).

  Form XXVI can be prepared by dissolving about 1: 7 (w / v) fluvastatin sodium Form B in a 20: 1 mixture of 1,4-dioxane: water. Reflux the mixture until a clear solution is obtained. The mixture is then cooled or allowed to cool to induce precipitation of fluvastatin sodium of type XXVI. Form XXVI can be separated from water and 1,4-dioxane by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated type XXVI is dried. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin sodium crystal form XXVII Fluvastatin sodium form XXVII has peaks characteristic of 3.3, 3.9, 15.9, 18.4, and 21.6 ± 0.2 degrees (2θ) and 8.4, 15.0, 17.9, 24.3, and 25.7 ± 0.2 degrees ( A PXRD diffractogram with another peak at 2θ) is given (Figure 50).

  The initial process for preparing Form XXVII is the same as the process for preparing Form XXVI. Form B is dissolved in a refluxing 20: 1 mixture of 1,4-dioxane: water. However, 1.5 times the amount of hexane is slowly added to the solution at reflux temperature. The mixture is then cooled to ambient temperature, after which sodium XXVII fluvastatin sodium crystallizes from the mixture. Form XXVII can be separated from the solution by conventional methods (eg filtration, decanting, centrifugation, etc., preferably filtration in an inert atmosphere such as nitrogen). The separated form XXVII is dried. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin sodium crystal XXIX type Fluvastatin sodium XXIX type has peaks characteristic of 4.4, 5.9, 6.8, 7.9, 10.8 ± 0.2 degrees (2θ), 14.3, 15.6, 17.5, 19.7, 21.3, 22.7 ± 0.2 degrees ( A PXRD diffractogram with another peak at 2θ) is given (FIG. 51).

  Fluvastatin sodium form XXIX is prepared by creating a heterogeneous mixture of fluvastatin sodium form XV and 1,4-dioxane and maintaining this heterogeneous mixture until virtually all form XV is converted to form XXIX can do. Preferably the conversion is accelerated by heating the heterogeneous mixture.

  Under a particularly preferred set of conditions, the heterogeneous mixture is heated to the reflux temperature of 1,4-dioxane and maintained at reflux for about 16 hours. Form XXIX is then separated from 1,4-dioxane by cooling the mixture and filtering the mixture under a stream of nitrogen. The XXIX type is then dried by conventional methods.

Fluvastatin sodium crystal XXX type Fluvastatin sodium XXX type has peaks characteristic of 5.4, 5.8, 10.8, 13.8, 14.8 ± 0.2 degrees (2θ), 16.4, 19.0, 19.5, 20.2, 20.8, 21.5, 22.7 ± 0.2 A PXRD diffractogram with another peak at degrees (2θ) is given (Figure 52). The moisture content of the sample measured by Karl Fischer is about 4% by weight. The weight loss by TGA is about 10%.

  Fluvastatin sodium form XXX can be prepared by producing a heterogeneous mixture of fluvastatin sodium form XV and one or a mixture of several selected organic liquids. Liquids that have been found to be suitable include methyl ethyl ketone (“MEK”), tetrahydrofuran (“THF”), acetone, butan-2-ol, and butan-1-ol. The heterogeneous mixture is maintained until substantially all XV types are converted to XXX types. Preferably the conversion is accelerated by heating the heterogeneous mixture.

  Under a particularly preferred set of conditions, the heterogeneous mixture is heated to the reflux temperature of the organic liquid and maintained at reflux for about 16 hours. The XXX form is then separated from the organic liquid by cooling the mixture and filtering the mixture under a stream of nitrogen. The XXX type is then dried by conventional methods.

  Fluvastatin sodium form XXX can also be prepared directly by precipitation from a lower alkyl ester of fluvastatin from a solution containing excess sodium. A suitable excess sodium is about 1.5 molar equivalents. In a preferred method, the starting material is added to a solution of sodium hydroxide in a mixture containing water as a minor component and methanol as a major component, and the resulting mixture is, for example, a solvent until a clear solution is obtained. To reflux temperature. Acetone is then added to the solution at high temperature to induce XXX type precipitation. After cooling to ambient temperature, type XXX can be separated from methanol and water by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably the water is separated under an inert gas such as nitrogen by vacuum filtration. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystal XXXI type Fluvastatin sodium XXXI type has peaks characteristic of 5.3, 6.1, 6.5, 11.9, 13.2 ± 0.2 degrees (2θ), and 8.0, 8.5, 9.3, 16.3, 18.3, 20.2, 20.6, 21.1 A PXRD diffractogram with other peaks at ± 0.2 degrees (2θ) is given (Figure 53). The water content of fluvastatin sodium XXXI measured by Karl Fischer analysis is about 16% by weight. The weight loss due to TGA is about 10% by weight. Fluvastatin sodium form XXXI is a tetrahydrate.

  Fluvastatin sodium form XXXI can be prepared by creating a heterogeneous mixture of fluvastatin sodium form XV and ethanol and maintaining this heterogeneous mixture until virtually all form XV is converted to form XXXI . Preferably the conversion is accelerated by heating the heterogeneous mixture.

  Under a particularly preferred set of conditions, the heterogeneous mixture is heated to the reflux temperature of ethanol and maintained at reflux for about 23 hours. Form XXXI is then separated from the ethanol by cooling the mixture and filtering the mixture under a stream of nitrogen. The XXXI type is then dried by conventional methods.

Fluvastatin sodium crystal XXXIII type Fluvastatin sodium XXXIII type has peaks characteristic of 4.0, 5.5, 8.0, 9.1, 13.4, 16.6, 21.2 ± 0.2 degrees (2θ) and 6.6, 8.8, 10.4, 11.6, 12.0, 14.1 , 14.8, 16.1, 17.9, 18.5, 19.7, 20.3, 24.3, 24.9, PXRD diffractograms with other peaks at 26.7 ± 0.2 degrees (2θ) are given (FIG. 54). The water content measured by Karl Fischer is about 7% by weight. The weight loss due to TGA is about 7% by weight. Fluvastatin sodium XXXIII form is dihydrate and hemipentahydrate.

  Fluvastatin sodium form XXXIII produces a heterogeneous mixture of fluvastatin sodium form XV or form B and ethanol (preferably absolute ethanol) and maintains the mixture for a time sufficient to achieve the desired yield of form XXXIII Can be prepared. The mixture is preferably stirred for about 5 hours to about 48 hours and heated to reflux temperature with stirring. The product is then recovered from the mixture by conventional methods (eg, filtration, decanting, centrifugation, etc.). The recovered wet product is then dried from time to time. Drying is performed at a suitable temperature range of about 40 ° C. to about 60 ° C. for about 12 to about 48 hours.

Fluvastatin sodium XXXIV type Fluvastatin sodium XXXIV type has characteristic peaks at 5.4, 6.1, 7.6, 18.5, 21.1 ± 0.2 degrees (2θ), 8.8, 9.3, 12.4, 13.1, 14.3, 15.2, 15.9, 17.2, PXRD diffractograms with other peaks at 17.6, 20.5, 22.2, 24.1, 25.4, 26.2 ± 0.2 degrees (2θ) are given (FIG. 55). The water content of type XXXIV measured by Karl Fischer analysis is about 10% by weight. The weight loss due to TGA is about 20% by weight.

  Fluvastatin sodium form XXXIV is prepared by generating a heterogeneous mixture of fluvastatin sodium form XV and dimethyl sulfoxide ("DMSO") and maintaining the mixture for a time sufficient to achieve the desired yield of form XXXIV can do. The mixture is preferably stirred for about 5 hours to about 48 hours and heated with stirring, more preferably about 80 ° C. or higher. The product is then recovered from the slurry by conventional methods (eg, filtration, decanting, centrifugation, etc.). The recovered wet product is then dried from time to time. Drying is performed at a suitable temperature range of about 40 ° C. to about 60 ° C. for about 12 to about 48 hours.

Fluvastatin sodium XXXV type Fluvastatin sodium XXXV type has characteristic peaks at 5.4, 6.0, 9.9, 14.8, 21.0 ± 0.2 degrees (2θ), and other peaks at 16.7, 18.6, 19.8, 22.6 ± 0.2 degrees (2θ) A PXRD diffractogram with peaks is given (Figure 56). The moisture content of type XXXIV measured by Karl Fischer is about 15% by weight. Weight loss by TGA is about 31% by weight. Fluvastatin sodium form XXXV is hemipentahydrate.

  Fluvastatin sodium form XXXV produces a heterogeneous mixture of fluvastatin sodium form XV and N, N-dimethylformamide (“DMF”), maintaining the mixture for a time sufficient to achieve the desired yield of form XXXV Can be prepared. The mixture is preferably stirred for about 5 hours to about 48 hours. The mixture is preferably heated with stirring. More preferably, the stirred mixture is heated to about 80 ° C. or higher. The product is then recovered from the mixture by conventional methods (eg, filtration, decanting, centrifugation, etc.). The recovered wet product is then dried from time to time. Drying is performed at a suitable temperature range of about 40 ° C. to about 60 ° C. for about 12 to about 48 hours.

Fluvastatin sodium crystal form XXXVI Fluvastatin sodium form XXXVI has characteristic peaks at 3.0, 9.2, 11.5, 14.4, and 20.2 ± 0.2 degrees (2θ), and others at 9.6, 12.3, and 12.8 ± 0.2 degrees (2θ) A PXRD diffractogram with a peak of is given (FIG. 56).

  Form XXXVI is prepared by suspending fluvastatin sodium Form XI-wet (after filtration but before drying) in water for a sufficient time to perform the conversion (typically about 6 hours). can do. The product is then recovered from the suspension by conventional methods (eg, filtration, decanting, centrifugation, etc.). Next, the collected wet product is dried as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystal form XXXVII Fluvastatin sodium form XXXVII has characteristic peaks at 3.63, 10.36, 13.74, 17.93, 18.34 ± 0.2 degrees (2θ), and 11.26, 12.16, 12.91, 19.44, 20.57 ± 0.2 degrees (2θ) Gives a PXRD diffractogram with other peaks (FIG. 58). The moisture content of this sample, measured by Karl Fischer, is about 9% by weight. Weight loss by TGA is about 31% by weight.

  Fluvastatin sodium form XXXVII can be prepared by producing a heterogeneous mixture of fluvastatin sodium form XI and water. The weight ratio of Form XI to water is preferably about 0.5: 1. The mixture is maintained at ambient temperature. The conversion takes about 5 hours and 45 minutes at 22 ° C. The XXXVII form can then be separated from the water by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the water is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystal XXXVIII type Fluvastatin sodium XXXVIII type has characteristic peaks at 3.64, 4.66, 7.30, 8.84, 11.61 ± 0.2 degrees (2θ), and 19.08, 19.65, 21.15, 22.59, 24.20 ± 0.2 degrees (2θ) Gives a PXRD diffractogram with other peaks (FIG. 59). The moisture content of this sample, measured by Karl Fischer, is about 6-7% by weight. The weight loss by TGA is about 10-11% by weight.

  Fluvastatin sodium form XXXVIII can be prepared by producing a heterogeneous mixture of fluvastatin sodium form XI and ethanol. In order to obtain the highest polymorphic purity product, it is preferred to use absolute ethanol. The ratio of Form XI to ethanol is preferably about 0.2 g / ml, more preferably about 0.19 g / ml.

  Under a particularly preferred set of conditions, the heterogeneous mixture is heated until the ethanol is boiled and maintained at this temperature for several hours until the conversion of Form XI to Form XXXVIII is complete. The conversion is followed by powder X-ray diffraction. If the conversion is not complete after a few hours (one of our experiments took 16 hours), the mixture can be maintained at elevated temperature or ambient temperature until the conversion is considered complete.

  The XXXVIII form can then be separated from ethanol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the ethanol is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  Fluvastatin sodium Form XXXVIII can also be prepared from the lower alkyl ester of fluvastatin by taking up about 1 molar equivalent of sodium hydroxide solution in ethanol and precipitating it by adding ethyl acetate to the mixture. The XXXVIII form can then be separated from ethanol and separated from ethanol and ethyl acetate by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably ethanol and ethyl acetate are separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  Furthermore, Form XXXVIII can be prepared by suspending fluvastatin sodium Form XI-wet in refluxing absolute ethanol, preferably for about 16 hours. The suspension is then cooled to a low temperature and the product is isolated by conventional methods.

Fluvastatin sodium crystals XXXIX type Fluvastatin sodium XXXIX type has peaks characteristic of 3.7, 4.5, 8.5, 17.8, 20.1 ± 0.2 degrees (2θ) and 6.9, 11.2, 16.8, 19.6, and 21.6 ± 0.2 degrees (2θ ) Gives a PXRD diffractogram with other peaks (FIG. 60).

  Form XXXIX can be prepared directly from lower alkyl esters of fluvastatin, such as fluvastatin methyl ester. This ester is dissolved in about 1 molar equivalent sodium solution in ethanol. Sodium is conveniently provided by dissolving an appropriate amount of sodium hydroxide pellets in water, taking care that dissolution in water is highly exothermic. This solution is heated for a time sufficient to hydrolyze the ester, typically several hours. A large amount (eg 8 × v / v) of propan-2-ol is then added to this solution. The mixture is then cooled to ambient temperature and maintained until a precipitate forms in the flask.

  Form XXXIX can be separated from the solution by conventional methods. Unlike type IX, type XXXIX can be obtained without the use of water.

Fluvastatin sodium crystal XLI type Fluvastatin sodium XLI type has characteristic peaks at 3.75, 4.31, 9.10, 11.00 ± 0.2 degrees (2θ), and other peaks at 5.60, 7.30, 7.55, 14.50, 18.04 ± 0.2 degrees (2θ) A PXRD diffractogram with a peak of is given (FIG. 61). The moisture content of this sample, measured by Karl Fischer, is about 9% by weight. The weight loss due to TGA is about 9% by weight. Fluvastatin sodium form XLI is hemipentahydrate.

  Fluvastatin sodium form XLI can be prepared by precipitating fluvastatin sodium from a mixture of water and acetonitrile. The water is heated to obtain a more concentrated solution of XLI and maximum recovery. Fluvastatin sodium can be dissolved to obtain a 0.375 g / ml or higher solution in water at 100 ° C. Of course, if all the fluvastatin sodium does not enter the solution or reprecipitate, add additional water. Once a homogeneous solution is formed, acetonitrile is added to the solution to induce precipitation of fluvastatin sodium. The addition takes place at any higher or higher temperature used to dissolve the starting material. The addition is performed dropwise, and it is generally necessary to add more acetonitrile than the amount of water used. For example, we used a slight excess of acetonitrile over 4 times. The resulting heterogeneous mixture is then allowed to cool. Before isolating the fluvastatin sodium XLI form to precipitate. Recovery can be improved by adding additional acetonitrile after cooling.

  The XLI type can then be separated from water and acetonitrile by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen and washed with acetonitrile. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystal type XLII Fluvastatin sodium XLII type has characteristic peaks at 3.4, 9.7, 11.0, 18.9 ± 0.2 degrees (2θ) and others at 5.7, 14.8, 16.1, 17.0, 22.6 ± 0.2 degrees (2θ) A PXRD diffractogram with a peak of is given (Figure 62). The water content of this sample, measured by Karl Fischer, is about 4% by weight. The weight loss due to TGA is about 5% by weight. Fluvastatin sodium XLII form is a monohydrate.

  Form XLII can be prepared from fluvastatin-diol by dissolving fluvastatin-diol in methyl ethyl ketone and then filtering the solution. Sodium hydroxide dissolved in methanol is then added to this solution and the solution is stirred at room temperature to obtain a gelatinous precipitate. The product is recovered by any conventional method (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In another method for preparing fluvastatin sodium Form XLII, fluvastatin diol is dissolved in methanol at reflux temperature and solid sodium hydroxide is added to this solution. The solution is stirred at room temperature to obtain a pasty viscous precipitate. Add ethyl acetate dropwise to the stirred solution. The solution is then cooled to form a slurry. The product is separated from the solution by any conventional method (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In yet another method for preparing fluvastatin sodium XLII form, fluvastatin diol is completely dissolved in dichloromethane and the solution is filtered. To this solution is added an ethanolic or methanolic solution of NaOH. The solution is stirred at room temperature to obtain a precipitate, and the product is separated from the solution by any conventional method (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline form XLIII Fluvastatin sodium XLIII form PXRD diffraction with peaks characteristic of 4.25, 5.29, 6.59, 8.60 ± 0.2 degrees (2θ) and other peaks at 12.75, 14.26 ± 0.2 degrees (2θ) The figure is given (Figure 63). The moisture content of this sample, measured by Karl Fischer, is about 9-11% by weight. The weight loss due to TGA is about 12% by weight.

  We have discovered two ways to create the XLII type. This can be made by adding propan-2-ol dropwise from an aqueous solution at high temperature to induce precipitation. The preferred method is similar to the method used to prepare Form XLI, but propan-2-ol is used instead of acetonitrile. We prepared an aqueous solution with a 3-fold excess of water (ml / g) relative to fluvastatin sodium. After obtaining a homogeneous solution, a 3-fold excess of propan-2-ol (ml / ml) with respect to water was added thereto at a high temperature. The initial addition of propan-2-ol at a high temperature causes the formation of XLIII type crystals. However, to maximize XLIII recovery, an approximately equal amount of another propan-2-ol is added after the mixture has cooled.

  In another method for preparing fluvastatin sodium Form XLIII, the lower alkyl ester of fluvastatin is dissolved in a solution containing about 1 molar equivalent of sodium hydroxide in water. Once a homogeneous solution of fluvastatin sodium is obtained, the addition of propan-2-ol induces precipitation of the sodium salt. The salt formation and the initial addition of propan-2-ol is preferably carried out at an elevated temperature (eg 70 ° C.). After cooling the solution to ambient temperature, additional propan-2-ol can be added to increase the recovery of XLIII type. The solution tends to gel. As described in the examples, the gel can be broken by reheating the mixture and then cooling again.

  The XLIII form is then separated from water and propan-2-ol using any of the methods described above using conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline form XLIV Fluvastatin sodium XLIV form peaks characteristic of 3.46, 4.05, 9.19, 10.14, 20.56 ± 0.2 degrees (2θ), and 6.26, 10.91, 11.12, 11.38, 15.98, 20.02, 22.21, 23.52 Gives a PXRD pattern with other peaks at 25.45 ± 0.2 degrees (2θ) (FIG. 64). The water content of this sample, measured by Karl Fischer, is about 4-6% by weight. The weight loss by TGA is about 8-10% by weight.

  Fluvastatin sodium Form XLIV can be prepared by producing a heterogeneous mixture of amorphous fluvastatin sodium in propan-2-ol. Preferably two are used in a ratio of about 20 ml / g. The suspension is heated to accelerate the conversion. After cooling, type XLIV can be separated from propan-2-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). A suitable drying condition for the separated product is 50 ° C. under vacuum.

  Alternatively, Form XLIV can be prepared directly from fluvastatin free acid. In a preferred embodiment of this method, the free acid is dissolved in acetone and a molar equivalent of ethanolic sodium (preferably prepared by dissolving an equivalent of sodium hydroxide in ethanol) is added to the solution and the resulting mixture is added. Until fluvastatin sodium Form XLIV precipitates. The XLIV form is then separated from acetone and ethanol by conventional methods and dried. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Type XLV Fluvastatin sodium XLV type has peaks characteristic of 3.7, 5.1, 10.7, 17.8, and 20.3 ± 0.2 degrees (2θ), and 6.2, 14.5, 21.6, 22.6, and 25.2 ± 0.2 degrees ( 2PX) gives a PXRD pattern with other peaks (Figure 65).

  Type XLV must be suspended in amorphous fluvastatin sodium in propan-2-ol at room temperature for sufficient time to convert to XLV type (this typically requires about 25 hours). Can be prepared. The XLV type can then be separated from propan-2-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with propan-2-ol as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Type XLVI Fluvastatin sodium XLVI type has peaks characteristic of 3.3, 3.5, 10.2, 11.2, and 21.1 ± 0.2 degrees (2θ), and 9.7, 12.1, 17.2, and 19.0 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 66).

  Form XLVI can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. This ester is dissolved in a solution of about 1 molar equivalent of sodium in ethanol. Sodium is conveniently provided by dissolving an appropriate amount of sodium hydroxide pellets in water, taking care that dissolution in water is highly exothermic. This solution is heated for a time sufficient to hydrolyze the ester, typically several hours. A large amount (eg 10 × v / v) of acetonitrile is then added to this solution to induce XLVI type precipitation. The resulting slurry is then cooled to ambient temperature and the XLVI form is separated from ethanol and acetonitrile by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Type XLVII Fluvastatin sodium XLVII type has peaks characteristic of 3.3, 10.2, and 18.0 ± 0.2 degrees (2θ) and others at 8.3, 10.8, 13.6, 20.7, and 21.3 ± 0.2 degrees (2θ) A PXRD pattern with multiple peaks is given (Figure 67).

  Fluvastatin sodium XLVII form can be prepared by exposing fluvastatin sodium XVIII to water vapor. Preferably Form XVIII is maintained at ambient temperature under an atmosphere of 80% relative humidity. A substantially complete conversion takes place in a few weeks, typically around 3.5 weeks.

Fluvastatin sodium crystalline XLVIII type Fluvastatin sodium XLVIII type has peaks characteristic of 4.5, 6.7, 7.0, 10.9, 19.1, 21.7 ± 0.2 degrees (2θ) and 8.9, 12.9, 13.1, 13.5, 15.2, 16.8, 17.6 18.3, 19.7, 20.6 ± 0.2 degrees (2θ), giving a PXRD pattern with other peaks. The water content of this sample, measured by Karl Fischer, is about 6-8% by weight. The weight loss due to TGA is about 8% by weight. Fluvastatin sodium XLII form is a dihydrate.

  Fluvastatin sodium Form XLVIII can be made by dissolving the lower alkyl ester of fluvastatin in a solution containing about 1 molar equivalent of sodium hydroxide in methanol. Once a homogeneous solution of fluvastatin sodium is obtained, the addition of acetonitrile induces precipitation of the sodium salt. Salt formation and acetonitrile addition are preferably performed at elevated temperatures. After cooling and standing for a sufficient time to complete crystallization, XLIII form can be separated from methanol and acetonitrile by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  Fluvastatin sodium XLVIII can also be prepared from fluvastatin sodium Form B. Fluvastatin sodium Form B is slurried in methanol at an elevated temperature for a time sufficient to convert to XLVIII form. The slurry is then cooled to ambient temperature and the XLVIII form is separated by conventional methods known to those skilled in the art (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In another method for preparing fluvastatin sodium XLVIII form, fluvastatin sodium form B is dissolved in methanol at room temperature and the solution is heated to reflux temperature to obtain a precipitate. Methanol stays in solution for a short time. The resulting slurry is cooled and stirred at room temperature, and the XLVIII form is separated by conventional methods known to those skilled in the art (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In another method for preparing fluvastatin sodium XLVIII form, fluvastatin diol is completely dissolved in methanol at reflux temperature and the solution is filtered to obtain a clear solution and heated to reflux again. Solid NaOH is added to the solution at reflux temperature to obtain a precipitate. The resulting slurry is cooled to room temperature to obtain a paste-like viscous mixture. The solution is stirred at room temperature to obtain Form XLVIII as a precipitate. XLVIII form is separated by conventional methods known to those skilled in the art (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystal type XLIX Fluvastatin sodium XLIX type has characteristic peaks at 3.5, 5.0, 12.1, 13.5, and 20.2 ± 0.2 degrees (2θ), and others at 6.3, 10.1, and 17.1 ± 0.2 degrees (2θ) A PXRD pattern with the peaks of is given (FIG. 69).

  XLIX form can be prepared from fluvastatin sodium form B. In a preferred method about 1: 8 (w / v) Form B is dissolved in methanol at ambient temperature. After dissolution, the solution is heated to reflux and then MTBE is slowly added to the reflux solution (added dropwise on a bench scale). The addition causes precipitation of fluvastatin XLIX from the solution. After precipitation, the suspension is cooled to ambient temperature and the XLIX form can be separated from methanol and MTBE by conventional methods known to those skilled in the art (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. For example, after washing with MTBE, the crystals can be dried. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Form L Fluvastatin Sodium Form L (50) has peaks characteristic of 6.48, 6.92, 9.72, 12.64, 21.49 ± 0.2 degrees (2θ) and 4.53, 12.06, 13.50, 14.79, 15.79, 16.32, A PXRD pattern with other peaks at 19.15 and 23.19 ± 0.2 degrees (2θ) is given (FIG. 70). The water content of this sample, measured by Karl Fischer, is about 5-6% by weight. The weight loss due to TGA is about 7% by weight. Fluvastatin sodium form L is sesquihydrate.

  Fluvastatin sodium Form L can be prepared by precipitation from a mixture of methanol and ethyl acetate. Any crystalline or amorphous fluvastatin sodium starting material is first dissolved in methanol. 1 g of fluvastatin sodium is dissolved in 7 ml or more of methanol at room temperature. The starting material can be dissolved at ambient or elevated temperature (eg, the boiling point of methanol). Once dissolved, L-type precipitation is induced by adding ethyl acetate dropwise at high temperature to the solution. The amount of ethyl acetate used is preferably about 3 times the amount of methanol. Once precipitation is initiated, the mixture is allowed to cool and after a time for further optional crystallization at ambient temperature, the L form is obtained from methanol and ethyl acetate by conventional methods (eg filtration, decanting, centrifugation, etc.). Can be separated. Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin Sodium Crystalline Type LI Fluvastatin sodium XLIX has characteristic peaks at 6.2, 10.8, 14.5, and 20.7 ± 0.2 degrees (2θ), and other peaks at 8.9, 11.5, and 23.1 ± 0.2 degrees (2θ) A PXRD pattern with is given (FIG. 71).

  Form LI can be prepared from fluvastatin sodium form B by the same method used to prepare form XLIX, using acetonitrile instead of MTBE.

Fluvastatin Sodium Crystalline Form LIII Fluvastatin Sodium XLIX type has characteristic peaks at 5.6, 6.3, 10.5, 20.9 ± 0.2 degrees (2θ), and other peaks at 14.3, 15.1, 15.6, and 17.1 ± 0.2 degrees (2θ) A PXRD pattern with peaks is given (Figure 72).

  Form LIII can be prepared from fluvastatin sodium form B by the same method used to prepare form XLIX, using acetonitrile instead of MTBE.

Fluvastatin sodium crystalline LIV type Fluvastatin sodium LIV type has characteristic peaks at 3.4, 10.4, 18.2, 19.6, 21.3 ± 0.2 degrees (2θ), and 6.9, 12.1, 13.8, 17.7, 19.0 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 73). The moisture content of this sample measured by Karl Fischer is about 11% by weight. The weight loss due to TGA is about 11% by weight. Fluvastatin sodium form L is a trihydrate.

  Fluvastatin sodium LIV type can be prepared by heating fluvastatin to an aqueous sodium hydroxide solution to obtain a suspension having a mud-like viscosity. The suspension can be stirred at room temperature and the product separated by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LV type Fluvastatin sodium LV type has characteristic peaks at 3.7, 5.0, 5.9, 12.2 ± 0.2 degrees (2θ), and other peaks at 5.6, 8.7, 10.1, 11.2 ± 0.2 degrees (2θ) Gives a PXRD pattern with The moisture content of this sample, measured by Karl Fischer, is about 7% by weight. The weight loss due to TGA is about 7% by weight. Fluvastatin sodium form L is a dihydrate.

  Fluvastatin sodium Form LV can be prepared by precipitation from a mixture of methanol and acetonitrile. Suitable mixtures contain about 10% to about 12%, more preferably about 12.5% by volume (methanol volume / acetonitrile volume × 100).

  A preferred method starts with a lower alkyl ester of fluvastatin. Fluvastatin ester is added to acetonitrile and the mixture is heated until the ester is dissolved. The solution is then cooled and a solution of sodium hydroxide in methanol is added thereto. The LV form can be separated from methanol and acetonitrile by conventional methods (for example, filtration, decantation, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LVI type Fluvastatin sodium LVI type has characteristic peaks at 3.4, 22.1, and 27.4 ± 0.2 degrees (2θ) and others at 6.8, 10.2, 13.6, 18.5, and 20.0 ± 0.2 degrees (2θ) A PXRD pattern with a peak of is given (FIG. 75).

  Form LVI can be prepared directly from lower alkyl ester derivatives of fluvastatin having ketal protecting groups on the β and δ hydroxyl groups (eg, acetonide protected fluvastatin methyl ester). The starting material is taken up in THF and acetonitrile and hydrolyzed with HCl, preferably 1.5% (aqueous) HCl. The time required will depend on the concentration of starting material and acid used, but can be readily measured by reaction tracking methods such as thin layer chromatography. A sufficient excess of NaOH is then added to neutralize the HCl. Then THF is distilled off and the residue is taken up in acetone. About 1 molar equivalent of sodium hydroxide is added to the solution. Over time, fluvastatin sodium precipitates as type LVI. The LVI type can be separated by conventional methods (eg, filtration, decantation, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline form LVII Fluvastatin sodium form LVII has peaks characteristic of 3.7, 5.0, 5.5, 10.1, 12.1 ± 0.2 degrees (2θ), and 8.6, 11.1, 14.9, 21.7, 22.8 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 76). The moisture content of this sample measured by Karl Fischer is about 2% by weight. The weight loss due to TGA is about 2% by weight. Fluvastatin sodium form L is hemihydrate.

  Fluvastatin sodium Form LVII can be prepared by producing a heterogeneous mixture of fluvastatin sodium Form VII and ethanol and maintaining the heterogeneous mixture until substantially all of the Form VII is converted to Form LVII. Preferably the ethanol is anhydrous (“absolute” and the suspension is maintained under dry conditions. Form LVII can be separated from ethanol by conventional methods (eg filtration, decanting, centrifugation, etc.) Preferably, ethanol is separated by vacuum filtration under an inert gas such as nitrogen, and suitable drying conditions for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LVIII type fluvastatin sodium LVIII type has peaks characteristic of 3.4, 3.8, 5.4, 5.7, 10.3 ± 0.2 degrees (2θ), 4.7, 7.2, 8.4, 11.5, 17.5, 20.4, 21.4, 23.1 A PXRD pattern with other peaks at ± 0.2 degrees (2θ) is given (Figure 77). The moisture content of this sample measured by Karl Fischer is about 4-5% by weight. The weight loss due to TGA is about 6-7% by weight.

  Fluvastatin sodium form LVIII can be prepared by producing a heterogeneous mixture of fluvastatin sodium and propan-2-ol and maintaining for a time sufficient to substantially convert fluvastatin sodium to form LVIII . A preferred starting material is fluvastatin sodium Form B. The conversion is accelerated by heating the suspension, preferably to the reflux temperature of the diluent. Form LVIII can be separated from propan-2-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LX form Fluvastatin sodium LX form has characteristic peaks at 5.6, 6.3, and 10.5 ± 0.2 degrees (2θ), and 4.1, 5.0, 11.0, 15.7, 17.2, and 19.6 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 78). Form LX is prepared by adding ethyl acetate to a methanolic solution of fluvastatin sodium. In the described embodiment, the solution is heated and then ethyl acetate is added in portions. The LX form is then precipitated, stirred and recovered by conventional methods.

Fluvastatin Sodium Crystalline LXIV Type Fluvastatin Sodium LXIV type has characteristic peaks at 5.8, 13.9, and 14.7 ± 0.2 degrees (2θ) and other peaks at 5.1, 9.3, 11.7, and 19.4 ± 0.2 degrees (2θ) A PXRD pattern with is given (FIG. 79).

  Form LXIV can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. Two different methods have been discovered. In a preferred embodiment of one method, about 0.1: 1 (w / v) of starting material is dissolved in methanol while the mixture is heated to reflux. Next, about 1 equivalent of sodium hydroxide is added to the refluxing solution. During hydrolysis, fluvastatin sodium begins to precipitate. After hydrolysis is complete (which can be measured by thin layer chromatography), the slurry is cooled to ambient temperature. Cooling causes the precipitate to redissolve. Acetone is then added to the solution to reprecipitate the LXIV form of fluvastatin sodium. The LXIV form can then be separated from methanol and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In another method for making the LXIV form, about 1:15 (w / v) of the starting lower alkyl ester of fluvastatin is dissolved in acetone. The solution is then added with excess sodium hydroxide dissolved in methanol. Over time, fluvastatin sodium precipitates out of solution as LXIV form. The LXIV type can be separated from acetone and methanol by conventional methods (for example, filtration, decantation, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXV type Fluvastatin sodium LXV type has characteristic peaks at 5.8, 13.9, and 14.7 ± 0.2 degrees (2θ) and other peaks at 5.1, 9.3, 11.7, and 19.4 ± 0.2 degrees (2θ) A PXRD pattern with is given (FIG. 80).

  Form LXV can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. In a preferred method, about 1: 7 (w / v) of starting material is dissolved in methanol containing about 1 equivalent of sodium at ambient temperature. After the mixture is clarified, approximately 6 volumes of propan-2-ol are added to induce precipitation of LXV form of fluvastatin sodium. The LXV form can then be separated from methanol and propan-2-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum. In this method, 5 times the amount of acetone can be used instead of 6 times the amount of propan-2-ol.

Fluvastatin sodium crystalline form LXVI fluvastatin sodium form LXVI has peaks characteristic of 3.6, 10.8, 17.8, 18.3, and 21.6 ± 0.2 degrees (2θ), and 7.2, 12.2, 14.4, and 25.5 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 81).

  We have been able to prepare LXVI form in a similar manner from several other crystalline forms of fluvastatin sodium. Generally, any fluvastatin sodium Form VI, B, or XV is dissolved in water at ambient or elevated temperature to obtain a clear solution. The solution is preferably refluxed for 1-2 hours and then cooled to ambient temperature or left to cool. After a certain time, form LXVI precipitates out of solution. LXVI type can be separated from water by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the water is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with water as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline form LXVII fluvastatin sodium form LXVII gives a PXRD pattern with characteristic peaks at 3.7 and 4.4 ± 0.2 degrees (2θ) and other peaks at 5.6 and 10.8 ± 0.2 degrees (2θ) ( (Figure 82).

  Form LXVII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. In a preferred method, about 1:15 (w / v) of starting material is dissolved in acetone. Excess sodium hydroxide in methanol is added to the mixture at ambient temperature and the mixture is maintained at ambient temperature until ester hydrolysis is complete. The LXVII form can then be separated from methanol and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, methanol and acetone are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXVIII form Fluvastatin sodium form LXVIII has characteristic peaks at 3.6, 5.9, 10.8, and 11.6 ± 0.2 degrees (2θ), and 9.3, 15.4, 17.0, 18.4, and 23.0 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 83).

  Form LXVIII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. In a preferred method, about 1:15 (w / v) of starting material is dissolved in acetone. To the solution is added excess sodium hydroxide in methanol. The solution is maintained at ambient temperature for a time sufficient to hydrolyze the ester, which can be measured by thin layer chromatography. The LXVIII form can then crystallize spontaneously or with cooling and can be separated from methanol and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, methanol and acetone are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXIX type Fluvastatin sodium LXIX type has peaks characteristic of 3.5, 5.7, 10.8, 18.2, and 21.6 ± 0.2 degrees (2θ) and 12.4, 14.7, 20.4, 22.4, and 25.4 ± 0.2 degrees ( 2PX) gives a PXRD pattern with other peaks (Figure 84).

  Form LXIX can be prepared by slurrying fluvastatin sodium Form VI in propan-2-ol at reflux temperature for a time sufficient to effect conversion. After cooling the solution, the LXIX form can be separated from propan-2-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably propan-2-ol is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with propan-2-ol as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXX form Fluvastatin sodium LXX form has characteristic peaks at 3.0, 3.4, 5.9, and 13.8 ± 0.2 degrees (2θ), and 8.2, 8.9, 18.6, 21.1, and 22.4 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 85).

  Form LXX can be prepared from fluvastatin sodium such as form LXVII by dissolving in water at reflux temperature and adding a 10-fold excess of acetone to induce precipitation of LXX form fluvastatin sodium. After cooling the resulting mixture to ambient temperature, Form LXX can be separated from water and acetone by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably water and acetone are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXI type Fluvastatin sodium LXXI type has characteristic peaks at 3.9, 7.8, 11.6, and 15.5 ± 0.2 degrees (2θ), and others at 9.2, 13.3, 19.0, and 23.2 ± 0.2 degrees (2θ) A PXRD pattern with a peak of is given (FIG. 86).

  For LXXI, reflux a 1: 1 (w / v) mixture of fluvastatin sodium LXVII and water, and then add excess acetone to maintain the mixture for a time sufficient to effect conversion to LXXI. Can be prepared. After cooling the resulting mixture to ambient temperature, Form LXXI can be separated from water and acetone by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably water and acetone are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXII form Fluvastatin sodium form LXXII has characteristic peaks at 3.7, 5.7, and 12.1 ± 0.2 degrees (2θ) and other peaks at 5.0, 10.8, 16.8, and 20.1 ± 0.2 degrees (2θ) A PXRD pattern with is given (FIG. 87).

  LXXII form can be prepared from fluvastatin sodium form VI. In one preferred method, the starting material is suspended in an approximately 40: 1 mixture of acetone and water and heated to reflux for a time sufficient to effect conversion to LXXII form. After cooling the mixture to ambient temperature, Form LXXII can be separated from water and acetone by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably water and acetone are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with acetone as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  In another preferred method, Form VI is suspended in acetonitrile and heated to reflux for a time sufficient to effect conversion. After cooling the mixture to ambient temperature, Form LXXII can be separated from acetonitrile by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably the acetonitrile is separated by vacuum filtration under an inert gas such as nitrogen. For example, after washing with acetonitrile as needed, the crystals can be dried. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXIV form Fluvastatin sodium form LXXIV has characteristic peaks at 4.0, 12.8, 19.0, 19.9, and 25.8 ± 0.2 degrees (2θ), and 5.4, 11.8, 13.4, 18.0, and 24.6 ± 0.2 degrees ( 2PX) gives a PXRD pattern with other peaks (Figure 89).

  Form LXXIV can be prepared from fluvastatin sodium Form B by suspending in an approximately 10: 1 mixture of propan-2-ol and water and refluxing for a time sufficient to effect conversion. After cooling the solution, Form LXXIV can be separated from propan-2-ol and water by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably propan-2-ol and water are separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with propan-2-ol as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXV form Fluvastatin sodium form LXXV has characteristic peaks at 4.4, 6.6, 10.8, 14.3, and 22.2 ± 0.2 degrees (2θ), and 7.8, 15.0, 19.8, 20.4, and 21.4 ± 0.2 degrees ( A PXRD pattern with other peaks at 2θ) is given (FIG. 90).

  Form LXXV can be prepared from fluvastatin sodium form XXX by refluxing form XXX in methanol for a time sufficient to effect conversion. After cooling the solution, the LXXV form can be separated from methanol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the methanol is separated by vacuum filtration under an inert gas such as nitrogen. For example, the crystals can be dried after washing with methanol as needed. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXVI form Fluvastatin sodium form LXXVI gives a PXRD pattern with characteristic peaks at 3.5, 7.0, 10.5, and 13.0 ± 0.2 degrees (2θ) (FIG. 91).

  Form LXXVI can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. In a preferred method, the starting material is dissolved in an approximately 5: 3 ethanol: water mixture containing approximately 1 equivalent of sodium hydroxide. After the hydrolysis is complete, the mixture is partially concentrated and additional water is added. The mixture is then extracted with a solvent that is not miscible with water (eg ethyl acetate). The aqueous phase is then distilled to leave a residue that is fluvastatin sodium form LXXVI.

Fluvastatin sodium crystalline LXXVII form Fluvastatin sodium form LXXVII has characteristic peaks at 3.6, 8.8, 11.0, 12.8, and 17.8 ± 0.2 degrees (2θ), and others at 7.3, 20.2, and 31.0 ± 0.2 degrees (2θ) A PXRD pattern with multiple peaks is given (Figure 92).

  Form LXXVII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. In a preferred method, 1:30 (w / v) starting material is dissolved in ethyl acetate. Add excess aqueous sodium hydroxide to the solution. The solution is maintained at ambient temperature for a time sufficient to hydrolyze the ester (which can be measured by thin layer chromatography). The LXXVII form can then be crystallized and separated from ethyl acetate and water by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, ethyl acetate and water are separated by vacuum filtration under an inert gas such as nitrogen. For example, after washing with ethyl acetate as needed, the crystals can be dried. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium crystalline LXXVIII form Fluvastatin sodium form LXXVIII has characteristic peaks at 8.8, 19.1, 27.2, 29.6, and 30.9 ± 0.2 degrees (2θ), and 3.4, 11.3, 17.7, 22.5, and 32.2 ± 0.2 degrees ( 2PX) gives a PXRD pattern with other peaks (Figure 93).

  Form LXXVIII can be prepared directly from lower alkyl esters of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with aqueous sodium hydroxide. The reaction mixture is then extracted with ethyl acetate. Concentrate the aqueous phase. The residue is then contacted with propan-2-ol or acetonitrile for 1 or 2 days. After separation of propan-2-ol or acetonitrile by conventional methods, fluvastatin sodium is in LXXVIII form. For example, after washing with acetonitrile as needed, the crystals can be dried. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Clear physical property summary of fluvastatin sodium crystal form
IV, IV-1, VI, VII, XI, XI-2, XVI to XVIII, XIX, XIX-1, XX, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVII, XXXVIII, XLI, XLII, XLIII, The moisture content of XLVIII, L, LIV, LV, LIV, LV, LVII, and LVIII types is shown in the table below.

  In addition to the crystalline polymorph of fluvastatin sodium, we have discovered a number of semi-crystalline solid forms of fluvastatin that can be obtained reproducibly by several methods described below.

Fluvastatin sodium form XC Fluvastatin sodium form XC gives a PXRD pattern with characteristic peaks at 3.2 and 9.6 ± 0.2 degrees (2θ) and other peaks at 11.8 and 19.8 ± 0.2 degrees (2θ) (FIG. 97). ).

  Fluvastatin sodium form XC can be prepared from fluvastatin sodium form B by dissolving it in ethanol at ambient temperature and then adding cyclohexane to induce precipitation. The XC form can then be separated from ethanol and cyclohexane by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCI Fluvastatin sodium type XCI has characteristic peaks at 4.7, 5.6, and 13.8 ± 0.2 degrees (2θ), and 7.3, 9.6, 10.8, 16.4, 17.6, 19.8, 20.8, and 23.1 ± 0.2 degrees A PXRD pattern having another peak at (2θ) is given (FIG. 98).

  Fluvastatin sodium form XCI can be prepared from fluvastatin sodium form XV by suspending form XV in ethyl acetate and maintaining the suspension at a high temperature for a time sufficient to convert form XV to form XCI. it can. After cooling the suspension to ambient temperature, Form XCI can be separated from ethyl acetate by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably, ethyl acetate is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCII Fluvastatin sodium type XCII has peaks characteristic of 3.4, 10.1, and 11.8 ± 0.2 degrees (2θ), and at 4.1, 17.8, 20.1, 21.7, 23.4, and 25.3 ± 0.2 degrees (2θ) A PXRD pattern with other peaks is given (Figure 99).

  Fluvastatin sodium form XCII can be prepared from fluvastatin sodium form B by dissolving it in 10: 1 ethanol: methanol at reflux temperature and then adding hexane to induce precipitation. XCII can then be separated from ethanol, methanol and cyclohexane by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCIII Fluvastatin sodium type XCIII has characteristic peaks at 4.9, 5.9, 7.2, and 12.3 ± 0.2 degrees (2θ) and other peaks at 9.7, 10.9, and 13.9 ± 0.2 degrees (2θ) A PXRD pattern is provided (Figure 100).

  Fluvastatin sodium form XCIII is suspended from fluvastatin sodium form XV in propan-1-ol at ambient temperature and the suspension is maintained at ambient temperature for a time sufficient to convert form XV to form XCIII Can be prepared. Form XCIII can be separated from propan-1-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably propan-1-ol is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCIV Fluvastatin sodium type XCIV has peaks characteristic of 4.6, 9.2, and 20.3 ± 0.2 degrees (2θ), and 4.1, 6.7, 13.0, 15.8, 17.7, 21.7, and 23.0 ± 0.2 degrees (2θ ) Is given a PXRD pattern with other peaks (FIG. 101).

  Fluvastatin sodium form XCIV is suspended from fluvastatin sodium form XV in butan-1-ol at ambient temperature and the suspension is maintained at ambient temperature for a time sufficient to convert form XV to form XCIII Can be prepared. XCIII can be separated from butan-1-ol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the butan-1-ol is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium XCV type Fluvastatin sodium XCV type has characteristic peaks at 5.7, 13.0, 19.8, and 20.5 ± 0.2 degrees (2θ), and other peaks at 4.2, 4.7, 12.3, and 15.9 ± 0.2 degrees (2θ) A PXRD pattern with peaks is given (FIG. 102).

  Fluvastatin sodium form XCV is a suspension from fluvastatin sodium form XV that is suspended at ambient temperature in ethyl acetate, acetone, 1,4-dioxane, or MEK, and the suspension is converted from form XV to form XCV. It can be prepared by maintaining at ambient temperature for a sufficient time. XCV type can be separated from the diluent by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the diluent is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCVI Fluvastatin sodium type XCVI has peaks characteristic of 3.7, 11.0, 12.9, and 18.2 ± 0.2 degrees (2θ), and 5.2, 8.3, 17.7, 21.5, and 25.5 ± 0.2 degrees (2θ) A PXRD pattern with other peaks is given (Figure 103).

  Fluvastatin sodium form XCVI is prepared from fluvastatin sodium form XV by suspending it in THF at ambient temperature and maintaining the suspension at ambient temperature for a time sufficient to convert form XV to form XCVI be able to. XCVI type can be separated from THF by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, the THF is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCVII Fluvastatin sodium type XCVII has a characteristic peak at 3.5 ± 0.2 degrees (2θ) and a PXRD pattern with other peaks at 9.4, 18.4, 20.0, 21.2, and 22.0 ± 0.2 degrees (2θ) (Fig. 104).

  Fluvastatin sodium Form XCVII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in cyclohexane. In a preferred method, sodium hydroxide is added as a methanolic solution. Over time, Form XCVII precipitates from the mixture. Form XCVII can be separated from cyclohexane by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably cyclohexane is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCVIII Fluvastatin sodium type XCVIII gives a PXRD pattern with characteristic peaks at 3.8 and 10.8 ± 0.2 degrees (2θ) and other peaks at 6.4 and 14.4 ± 0.2 degrees (2θ) (FIG. 105). ).

  Fluvastatin sodium form XCVIII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in concentrated methanol solution. After completion of the hydrolysis, a large excess of acetonitrile (eg ˜7 ×) is added to methanol at high temperature. The hot solution is cooled or allowed to cool and is maintained until Form XCVIII precipitates from the solution. Form XCVIII can be separated from methanol and acetonitrile by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, methanol and acetonitrile are separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type XCIX Fluvastatin sodium type XCIX has PXRD patterns with characteristic peaks at 3.6, 5.3, 8.7, and 10.4 ± 0.2 degrees (2θ), and other peaks at 17.9 and 21.5 ± 0.2 degrees (2θ) (FIG. 106).

  Fluvastatin sodium form XCIX is prepared from fluvastatin sodium form VI by suspending it in ethanol at ambient temperature and maintaining the suspension at ambient temperature for a time sufficient to convert form VI to form XCIX be able to. XCIX can be separated from ethanol by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the ethanol is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type C Fluvastatin sodium type C (100) has characteristic peaks at 3.3, 9.8, 11.0, 19.0, and 22.7 ± 0.2 degrees (2θ), and 6.2, 17.2, and 21.3 ± 0.2 degrees (2θ) Gives a PXRD pattern with other peaks (FIG. 107).

  Form C can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in dichloromethane. Over time, fluvastatin sodium precipitates from the reaction mixture as Form C. Form C can be separated from dichloromethane by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the dichloromethane is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type CI Fluvastatin sodium type CI gives a PXRD pattern with characteristic peaks at 4.5 and 11.2 ± 0.2 degrees (2θ) and other peaks at 5.7 and 19.3 ± 0.2 degrees (2θ) (Figure 108). ).

  Form CI can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a mixture of acetone and methanol. After completion of the hydrolysis, it is cooled appropriately to ambient temperature and the CI form precipitates from the reaction mixture. CI type can be separated from methanol and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, methanol and acetone are separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type CII Fluvastatin sodium type CII gives a PXRD pattern with characteristic peaks at 4.3 ± 0.2 degrees (2θ) and other peaks at 8.7, 11.0, and 19.2 ± 0.2 degrees (2θ) (Figure 109).

  Form CII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a mixture of acetone and methanol. After completion of the hydrolysis, it is cooled to ambient temperature as appropriate and Form CII precipitates from the reaction mixture. Type CII can be separated from methanol and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, methanol and acetone are separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type CIII Fluvastatin sodium type CIII has characteristic peaks at 4.5, 20.4, 25.9, and 30.6 ± 0.2 degrees (2θ), and at 5.6, 10.1, 12.5, 19.0, and 19.7 ± 0.2 degrees (2θ) A PXRD pattern with other peaks is given (FIG. 110).

  Form CIII can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a mixture of acetone and water. After completion of the hydrolysis, it is appropriately cooled to ambient temperature and Form CIII precipitates from the reaction mixture. Form CIII can be separated from water and acetone by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably water and acetone are separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium type CIV Fluvastatin sodium type CIV has peaks characteristic of 3.7, 9.7, 18.3, 19.9, 21.8 ± 0.2 degrees (2θ) and other peaks at 5.6, 11.3, 14.8, 22.6 ± 0.2 degrees (2θ) A PXRD pattern with peaks is given (Figure 111). Form CIV can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in THF. After completion of the hydrolysis, hexane is added to the reaction mixture to induce a CIV type precipitation. Type CIV can be separated from THF by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably, the THF is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Fluvastatin sodium CV type Fluvastatin sodium CV type has peaks characteristic of 3.7, 8.9, 19.1, 22.5, 29.7 ± 0.2 degrees (2θ) and 11.5, 17.0, 25.1, 26.9, 28.2 ± 0.2 degrees (2θ) A PXRD pattern with other peaks is given (FIG. 112). Form CV can be prepared directly from a lower alkyl ester of fluvastatin, such as fluvastatin methyl ester. The starting material is hydrolyzed at high temperature with sodium hydroxide in acetonitrile. After completion of the hydrolysis, the reaction mixture is cooled or left to cool. Over time, fluvastatin sodium precipitates as CV type. The CV type can be separated from acetonitrile by conventional methods (for example, filtration, decantation, centrifugation, etc.). Preferably the acetonitrile is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Method for Preparing Amorphous Fluvastatin Sodium We have discovered that fluvastatin sodium precipitates from 1,4-dioxane and cyclohexane in an amorphous state. Thus, one suitable method for making the amorphous fluvastatin sodium of the present invention is to dissolve fluvastatin sodium in 1,4-dioxane, preferably at elevated temperature, more preferably at about 85 ° C., resulting in a solution To induce precipitation of amorphous fluvastatin sodium.

  In another preferred method, the lower alkyl ester of fluvastatin is suspended in cyclohexane. The desired amount of about 1 molar equivalent of sodium hydroxide is then added to the suspension in a minimum amount of protic solvent (eg methanol). The suspension clarifies upon addition. On standing, fluvastatin sodium precipitates out of solution in an amorphous form. If it does not precipitate, add additional cyclohexane to induce precipitation.

  In each of the above methods, the precipitate can be separated from 1,4-dioxane or cyclohexane by conventional methods (eg, filtration, decanting, centrifugation, etc.). Preferably, 1,4-dioxane is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

Pharmaceutical compositions and dosage forms containing the novel fluvastatin sodium form, and therapeutic methods using the same Fluvastatin exhibits antihypercholesterolemia and antihyperlipidemia action in mammals, particularly humans. Therefore fluvastatin sodium I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV and their mixtures with each other, as well as with other crystalline forms of fluvastatin sodium, are atherogenic It is useful for delivering fluvastatin to the digestive tract, bloodstream, and liver of humans and other mammals suffering from or at risk for arteriosclerosis. In particular, they are useful as active ingredients in pharmaceutical compositions and dosage forms. For this purpose they are formulated into various compositions and dosage forms for administration to humans and animals.

  The pharmaceutical composition of the present invention comprises fluvastatin sodium I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII. , XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI , XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII , LXXVIII, XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV and their mixtures with each other, and other crystalline forms of fluvastatin A mixture with sodium is optionally contained in a mixture with one or more other active ingredients. In addition to the active ingredient, the pharmaceutical composition of the present invention may contain one or more excipients. Excipients are added to the composition for various purposes.

  Diluents increase the bulk of a solid pharmaceutical composition and make it easier for a patient or caregiver to handle a pharmaceutical dosage form containing the composition. Solid composition diluents include, for example, microcrystalline cellulose (Avicel®), microfine cellulose, lactose, starch, pregelatinized starch starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, Dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit®), potassium chloride, powdered cellulose, chloride There are sodium, sorbitol, and talc.

  Solid pharmaceutical compositions that are formed into dosage forms such as tablets have excipients that include their function to help the active ingredient or other excipients bind after compression. Binders for solid pharmaceutical compositions include gum arabic, alginic acid, carbomers (eg carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (eg crucelle) (Klucel®), hydroxypropyl methylcellulose (eg Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (eg Kollidon ( (Registered trademark), Plasdone (registered trademark)), pregelatinized starch starch, sodium alginate, and starch.

  The dissolution rate of the shaped solid pharmaceutical composition in the patient's stomach is increased by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg, Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, Kollidon (registered trademark), polyplastidone (registered trademark), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium glycolic acid There are starches (eg Explotab®), and starches.

  Direct hitting lubricants may be added to improve the flowability of the non-shaped solid composition and improve the accuracy of administration. Excipients that function as direct hit lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

  When a tablet-like dosage form is made by compression of a powder composition, the composition is subjected to pressure from a punch and die. Some excipients and active ingredients tend to adhere to the surface of the punch or die, which causes dents and other surface disturbances in the product. Lubricants may be added to the composition to reduce adhesion and facilitate product release from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, PEG, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate , Stearic acid, talc, and zinc stearate.

  Flavoring agents and seasonings improve the taste of the dosage form for the patient. Common flavoring agents and seasonings for the drugs included in the compositions of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

  The solid and liquid compositions may also be colored using any pharmaceutically acceptable colorant to improve appearance and / or make it easier for the patient to identify product and unit dosage levels. .

  In the liquid pharmaceutical composition of the present invention, fluvastatin sodium I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII , XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI , XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII , Form LXXVIII and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, PEG, propylene glycol or glycerin.

  Liquid pharmaceutical compositions may contain an emulsifier to uniformly disperse the active ingredient or other excipients that are not soluble in the liquid carrier in the composition. Emulsifiers useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

  The liquid pharmaceutical composition of the present invention may also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such materials include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone , Propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

  Sweetening agents such as sorbitol, saccharin, saccharin sodium, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

  To improve storage stability, preservatives and chelating agents (eg, alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid) may be added at levels safe for digestion.

  The liquid composition of the present invention may also contain a buffer (eg, gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate).

  The choice and use of excipients can be readily determined by formulation scientists based on experience and consideration of standard methods and related research in this field.

  Solid compositions of the present invention include powders, granules, agglomerates, and compressed compositions. Dosage forms include oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation and ophthalmic administration. The most suitable route in a particular case depends on the nature and severity of the condition being treated, but the most preferred route of the present invention is oral. Dosages are conveniently provided in unit dosage forms and are prepared by any method known in the pharmaceutical arts.

  Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, troches, and liquid syrups, suspensions and elixirs.

  Particularly preferred dosage forms of the present invention are capsules containing the composition (preferably the powder or granular solid composition of the present invention) in a hard shell or soft shell. The shell is made from gelatin and optionally contains plasticizers (eg, glycerin and sorbitol) and opacifiers or colorants. Particularly preferred capsule fillings contain the excipients magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and talc in addition to one or more of the fluvastatin sodium crystalline forms of the present invention.

  Other particularly suitable dosage forms of the invention include excipient microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium bicarbonate, povidone, stearic acid, in addition to one or more fluvastatin sodium crystalline forms of the invention A compressed tablet containing magnesium, iron oxide yellow, titanium dioxide, and polyethylene glycol 8000.

  The active ingredient and excipients are formulated into compositions and dosage forms according to methods known in the art.

  A composition for tableting or capsule filling is prepared by wet granulation. In wet granulation, some or all of the active ingredient and powder type excipients are mixed and then further mixed in the presence of a liquid (typically water) that causes the powder to harden into granules. . The granules are screened and / or ground, dried and then screened and / or ground to the desired particle size. The granulate is then tableted or tableted after adding other excipients (eg, direct lubricant and / or lubricant).

  Tablet compositions are conveniently prepared by dry blending. For example, the active agent and excipient mixture composition is compressed into slugs or sheets and then crushed into compressed granules. The compressed granules are compressed into tablets.

  As an alternative to dry granulation, the mixed composition is compressed directly into a compressed dosage form using a direct compression method. Direct compression gives a more uniform tablet without granules. Excipients that are particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silicon. The correct use of these and other excipients in direct compression tablets is known to those skilled in the art having experience and skill in the specific problems of direct compression tablet formulation.

  The capsule filling of the present invention comprises any of the aforementioned blends and granules described for tableting, but does not undergo a final tableting process.

  Capsules, tablets and lozenges, and other dosage forms preferably contain a dose equivalent to about 10 to about 100 mg of fluvastatin. Preferably the dosage is equivalent to about 20 to about 80 mg of fluvastatin. More particularly, immediate release or uncontrolled release dosage forms preferably contain about 20 to about 40 mg equivalents of fluvastatin, and extended release dosage forms preferably about 60 to about 100 mg equivalents of fluvastatin, more preferably about 80 mg. Contains the equivalent of fluvastatin.

Preparation Method of Fluvastatin Sodium Crystalline Form B In another embodiment, the present invention provides a known preparation method of fluvastatin B form. In this method fluvastatin free acid, lactone, or a mixture of the two is dissolved in a solution containing about 1 molar equivalent of sodium hydroxide in a mixture of water and methanol. The most preferred solvent is a 10: 1 mixture of methanol: water. Conversion of lactones that may be present in the starting material can be followed by HPLC. Once a homogeneous solution of fluvastatin sodium is obtained, the addition of methyl tert-butylethyl (“MTBE”) induces precipitation of the sodium salt. The salt formation and the initial addition of MTBE are preferably carried out at an elevated temperature, for example at the reflux temperature of the solvent system. Form B can be separated from methanol, water and MTBE by conventional methods (eg filtration, decanting, centrifugation, etc.). Preferably the liquid is separated by vacuum filtration under an inert gas such as nitrogen. A suitable drying condition for the separated product is 50 ° C. under vacuum.

  Although the present invention has been described with reference to several preferred embodiments, the fluvastatin sodium I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, of the present invention, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV and B types The preparation methods and methods suitable for their identification are further illustrated in the following examples. These examples are for illustrative purposes only and do not limit the invention in any way.

Example
General powder X-ray diffraction data was obtained using methods known in the art on a SCINTAG powder X-ray diffractometer model X'TRA equipped with a semiconductor detector. 1.5418mm of copper radiation was used. A round aluminum sample holder with zero background was used.

  DSC analysis was performed on a Mettler 821 Star e. The sample weight was about 5 mg and the sample was at 30 ° C. to 200 ° C. at a rate of 10 ° C./min. The oven was constantly purged periodically with 40 ml / min nitrogen gas. A standard 40 μl aluminum crucible covered with a lid with 3 holes was used.

  TGA analysis was performed using a Mettler M3 meter. The sample weight was approximately 10 mg; the sample was scanned from 25 ° C. to 200 ° C. at 10 ° C./min. A standard 70 μl aluminum crucible covered with a lid with one hole was used.

IR analysis was performed using a Perkin Elmer “Spectrum One” FT-IR spectrometer in DRIFTt mode. Samples of 4000 to 400 ^-1 interval were scanned 16 times with 4.0 cm ^-1 resolution.

  The water content of fluvastatin sodium is measured by methods known in the art, such as the Karl Fischer method or thermogravimetric analysis.

Those skilled in the art will recognize that the abbreviations used in this disclosure are widely used in the fields of medicine and organic chemistry. Abbreviations used include:
ACN: Acetonitrile
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
EtOH: ethanol
Et ₂ O: diethyl ether
EtOAc: ethyl acetate
IPA: Isopropyl alcohol
MeOh: Methanol
MTBE: Methyl tert-butyl ether
MEK: Methyl ethyl ketone
THF: tetrahydrofuran

All preparations described below were performed on fluvastatin sodium Form B unless otherwise stated. Fluvastatin sodium XIX-1, XXXIII, XXXIV, and XXXV were purchased from Zhejiang Hisun Pharmaceutical Co., Limited (46 Waisha Rd., Jiaojiang District, Taizhou City, Zhejiange Province, China) Prepared using the starting material fluvastatin sodium Form XV.

1) Preparation of fluvastatin sodium crystal form I
Example 1
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) and NaOH (0.29 g) partially dissolved in acetone (0.75 ml) was added. The mixture was stirred overnight at room temperature. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.31 g (76.2%) fluvastatin sodium crystalline Form I.

Example 2
Fluvastatin methyl ester (3.01 g) was dissolved by heating in acetonitrile (60 ml), and NaOH (0.28 g) was added. The mixture was stirred at about 60 ° C. for 1 hour, cooled to room temperature, heated again to about 75 ° C., then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.07 g (34.9%) fluvastatin sodium crystalline Form I.

Example 3
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating, and NaOH (0.28 g) aqueous solution (0.75 ml) was added at about 50 ° C. The mixture was stirred at about 40 ° C. for 2 hours, cooled to room temperature and stirred for an additional hour. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.52 g (82.2%) fluvastatin sodium crystalline Form I.

Example 4
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in acetone (600 ml) at reflux temperature. The resulting solution was filtered and MTBE (200 ml) was added at reflux temperature. The solution was cooled to room temperature and MTBE (100 ml) was added. The mixture was concentrated under reduced pressure to give a precipitate. The product was then filtered, washed with MTBE (2 × 18 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.7 g (58%) of fluvastatin sodium crystalline Form I.

Example 5
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-2-ol (60 ml) and water (6 ml) at reflux temperature. The solution was cooled to 15 ° C. for 2 hours to obtain a precipitate. The product was then filtered under a stream of nitrogen, washed with butan-2-ol (1 × 15 ml), dried in a vacuum oven at 50 ° C. for 24 hours, and 0.05 g (2%) of fluvastatin sodium crystals I Got the mold.

2) Preparation of fluvastatin sodium crystal form II
Example 6
Fluvastatin sodium crystal Form B (3.0 g) was almost completely dissolved in butan-1-ol (90 ml) at reflux temperature. The mixture was stirred at reflux temperature for 2.5 hours. It was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered, washed with butan-1-ol (1 × 5 ml) and dried in a vacuum oven at 50 ° C. for 52 hours to give 1.7 g (56%) of fluvastatin sodium crystal Form II.

3) Preparation of fluvastatin sodium crystal form III
Example 7
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. MTBE (70 ml) was added dropwise and the mixture was stirred at reflux for 3 hours. The solution was cooled to room temperature, MTBE (70 ml) was added and a large amount of precipitate was obtained after 2 hours. The product was filtered, washed with MTBE (3 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.5 g (49%) of fluvastatin sodium crystal Form III.

Example 8
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. The solution was filtered and n-hexane (70 ml) was added dropwise. The mixture was stirred at reflux temperature for 3.5 hours. The solution was cooled to room temperature to obtain a precipitate. The product was filtered, washed with n-hexane (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 1.0 g (34%) of fluvastatin sodium crystal Form III.

Example 9
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (70 ml) at reflux temperature. The solution was cooled to room temperature to obtain a precipitate. The product was filtered, washed with 1,4-dioxane (1 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.2 g (75%) of fluvastatin sodium crystal Form III.

Example 10
A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate (150 ml) was stirred at reflux temperature. Hexane (150 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for 3 hours. The suspension was cooled to room temperature. The product was filtered under a stream of nitrogen, washed with hexane (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.7 g (91%) of fluvastatin sodium crystal Form III.

Example 11
Amorphous fluvastatin sodium (1.7 g) was dissolved in ethanol (10 ml) at reflux temperature. After 0.5 hours, the product was recrystallized at reflux temperature. The suspension was stirred for an additional hour at reflux temperature. The suspension was then cooled to room temperature and an additional amount of ethanol (10 ml) was added. The product was filtered under a stream of nitrogen, washed with ethanol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.9 g (53%) of fluvastatin sodium crystal form III.

Example 12
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (50 ml) at reflux temperature. Cyclohexane (65 ml) was added dropwise at reflux temperature to obtain a precipitate. The mixture was cooled to room temperature. The product was filtered, washed with cyclohexane (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 19.5 hours to give 2.7 g (91%) of fluvastatin sodium crystal Form III.

Example 13
A suspension of fluvastatin sodium crystal form XIV (3.0 g) was stirred in ethanol (20 ml) at reflux temperature for 7 hours. The suspension was cooled to room temperature. The product was filtered under a stream of nitrogen, washed with ethanol (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 2.3 g (77%) of fluvastatin sodium crystal form III.

4) Preparation of fluvastatin sodium crystal form IV
Example 14
Fluvastatin sodium (3.0 g) was dissolved in tetrahydrofuran (THF) (50 ml) at reflux temperature. Chloroform (50 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 40 minutes. A precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with chloroform (2 × 20 ml) and dried in a vacuum oven for 19 hours at 50 ° C. to give 2.7 g (89%) of fluvastatin sodium crystal Form IV It was.

Example 15
Fluvastatin sodium (3.0 g) was dissolved in tetrahydrofuran (THF) (50 ml) at reflux temperature. Dichloromethane (65 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 1 hour. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with dichloromethane (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 20 hours to give 2.6 g (87%) of fluvastatin sodium crystal Form IV It was.

Example 16
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature. 1,2-dichloroethane (50 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 1 hour. A precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.7 g (24%) of fluvastatin sodium crystal Form IV.

Example 17
Fluvastatin sodium (3.0 g) was dissolved in tetrahydrofuran (THF) (50 ml) at reflux temperature. Diethyl ether (50 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 1 hour. A precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with diethyl ether (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24.5 hours to give 2.1 g (69%) of fluvastatin sodium crystal Form IV. Obtained.

Example 18
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature. n-Pentane (50 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 8 minutes. A large amount of precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with n-pentane (2 × 25 ml), dried in a vacuum oven at 50 ° C. for 25 hours, and 2.8 g (93%) of fluvastatin sodium crystal Form IV Got.

Example 19
Fluvastatin sodium (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. Cyclohexane (70 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 3 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with cyclohexane (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 25.5 hours to give 2.1 g (69%) of fluvastatin sodium crystal Form IV.

Example 20
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (50 ml) at reflux temperature. Cyclohexane (70 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 3.5 hours. A precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with cyclohexane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 2.7 g (89%) of fluvastatin sodium crystal Form IV.

Example 21
Fluvastatin sodium (3.0 g) was dissolved in propan-2-ol (70 ml) at reflux temperature. MTBE (70 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 15 minutes. A precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with MTBE (3 × 20 ml) and dried in a vacuum oven at 50 ° C. for 25.5 hours to give 2.4 g (81%) of fluvastatin sodium crystal Form IV It was.

5) Preparation of fluvastatin sodium crystal form IV-1
Example 22
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature. n-Pentane (50 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 1 hour. A large amount of precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with n-pentane (2 × 50 ml), dried in a vacuum oven at 50 ° C. for 24 hours to give 2.9 g (97%) of fluvastatin sodium crystals IV− Obtained type 1.

Example 23
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallised. Cyclohexane (70 ml) was added at reflux temperature and the resulting mixture was stirred at this temperature for 5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with cyclohexane (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.0 g (100%) of fluvastatin sodium crystal Form IV-1 .

Example 24
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (75 ml) at reflux temperature. MTBE (75 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 4 hours. A large amount of precipitate was obtained during reflux. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with MTBE (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.7 g (89%) of fluvastatin sodium crystal Form IV-1. .

6) Preparation of fluvastatin sodium crystal form V
Example 25
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. The solution was filtered and n-heptane (70 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for a further 3 hours. The mixture was cooled to room temperature and stirred at this temperature for 25 hours. The product was isolated by filtration, washed with n-heptane (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.8 g (61%) of fluvastatin sodium crystalline Form V .

Example 26
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in a mixture of ethanol (50 ml), ethyl acetate (20 ml) and propan-1-ol (10 ml) at reflux temperature. The solution was filtered and n-hexane (200 ml) was added dropwise. The mixture was cooled to room temperature and stirred at this temperature for 16 hours. The product was isolated by filtration under a stream of nitrogen, washed with n-hexane (2 × 25 ml), dried in a vacuum oven at 50 ° C. for 24 hours, and 2.3 g (77%) of fluvastatin sodium crystals Form V Got.

7) Preparation of fluvastatin sodium crystal form VI
Example 27
Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at room temperature. Diethyl ether (100 ml) was added slowly at room temperature and the resulting mixture was stirred at this temperature for 1 hour. The mixture was then cooled using an ice bath. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.7 g (55%) of fluvastatin sodium crystal Form VI.

Example 28
Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at room temperature. Hexane (10 ml) was then added. Solvent and antisolvent were evaporated to dryness and the resulting solid was suspended in DMF (80 ml) at room temperature for 16 hours. The mixture was cooled using an ice bath. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.3 g (42%) of fluvastatin sodium crystals Forms VI and VII.

Example 29
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at 60 ° C. for 4 hours and no more starting material was detected by HPLC. Acetonitrile (58 ml) was then added dropwise over 1.5 hours. The solution became cloudy and was slowly cooled to room temperature. The mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.23 g (73%) of fluvastatin sodium crystal Form VI.

Example 30
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq) in methanol (5 ml). The mixture was heated to reflux and stirred for 2.25 hours and no more starting material was detected by HPLC. Next, acetonitrile (40 ml) was added dropwise in two portions over 1.5 hours. The mixture was slowly cooled to room temperature and stirred for an additional 1.75 hours. The product was isolated by filtration under nitrogen, washed with acetonitrile (20 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 1.7 g (83.4%) of fluvastatin sodium crystal Form VI.

Example 31
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq) in ethanol (15 ml). The mixture was stirred at about 70 ° C. for 1.75 hours and no more starting material was detected by HPLC. Acetone (40 ml) was then added dropwise to the solution, cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.54 g (75.6%) fluvastatin sodium crystal Form VI.

Example 32
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq) in water (0.5 ml) and butan-1-ol (8 ml). The mixture was stirred at about 80 ° C. for 4 hours and no more starting material was detected by HPLC. Acetonitrile (40 ml) was then added dropwise to the solution and the mixture was slowly cooled to room temperature and further stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (15 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium crystal Form VI (1.65 g, 81%).

8) Preparation of fluvastatin sodium crystal form VII
Example 33
Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at room temperature. Chloroform (100 ml) was added slowly at room temperature and the resulting mixture was stirred at this temperature for 4 hours. The mixture was then cooled using an ice bath. The product was isolated by filtration under nitrogen, washed with dichloromethane (1 × 35 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.0 g (65%) of fluvastatin sodium crystalline Form VII It was.

Example 34
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature. MTBE (100 ml) was added slowly at room temperature and the resulting mixture was stirred at this temperature for 5 hours. The mixture was then cooled using an ice bath. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 22 minutes to give 1.8 g (59%) of fluvastatin sodium crystalline Form VII.

Example 35
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature. Dichloromethane (100 ml) was added slowly at room temperature and the resulting mixture was stirred at this temperature for 16 hours. The mixture was then cooled using an ice bath. The product was isolated by filtration under nitrogen and dried for 23 minutes in a vacuum oven at 50 ° C. to give 2.4 g (79%) of fluvastatin sodium crystalline Form VII.

Example 36
Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at room temperature. Cyclohexane (20 ml) was then added. The solvent and antisolvent were evaporated to dryness and the resulting solid was suspended in DMF (80 ml) at room temperature for 16 hours. The mixture was cooled using an ice bath. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 23 minutes to give 1.9 g (64%) of fluvastatin sodium crystalline Form VII.

Example 37
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature. 1,2-Dichloroethane (100 ml) was added slowly at room temperature and the resulting mixture was stirred at this temperature for 5 hours. The mixture was then cooled using an ice bath. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 21 hours to give 1.8 g (60%) of fluvastatin sodium crystal Form VII.

Example 38
Fluvastatin sodium (3.0 g) was suspended in DMF (40 ml) at room temperature for 16 hours. The product was isolated by filtration under nitrogen, washed with DMF (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 28 hours to give 1.1 g (37%) of fluvastatin sodium crystalline Form VII It was.

Example 39
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq) and butan-1-ol (15 ml). When the mixture was stirred at about 80 ° C. for 1.5 hours, no starting material was detected by HPLC. Then 40 ml of acetone was added dropwise to the solution and the mixture was slowly cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.09 g (53.5%) fluvastatin sodium Form VII.

Example 40
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq) and butan-1-ol (15 ml). When the mixture was stirred at about 80 ° C. for 2.5 hours, no starting material was detected by HPLC. Then 40 ml of acetonitrile was added dropwise to the solution. The mixture was slowly cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (45 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.96 g (96.2%) of fluvastatin sodium Form VII.

Example 41
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq) in water (0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated to reflux and 1 ml propan-2-ol was added. After 2 hours, the mixture was cooled to room temperature and stirred for 2 hours. MTBE (60 ml) was added dropwise to the solution over 20 minutes, and the mixture was further stirred for 1.5 hours. The product was isolated by filtration under nitrogen, washed with MTBE, and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.9 g (62%) of fluvastatin sodium Form VII.

Example 42
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq) in methanol (30 ml). The mixture was stirred at room temperature for 4.5 hours. This was then filtered and concentrated by vacuum distillation until a solid appeared. The concentrated solution was heated to reflux and 60 ml of acetonitrile was added dropwise to the solution over 50 minutes. Turbidity was observed and the mixture was slowly cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (60 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium Form VII (2.54 g, 83.1%).

Example 43
Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) and heated to about 40 ° C. to dissolve the mixture. When added to a solution of NaOH (1 eq) in ethanol (7.5 ml), turbidity was immediately observed. The mixture was then heated to about 65 ° C. The mixture was slowly cooled to room temperature at room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium Form VII (1.99 g, 64.9%).

9) Preparation of fluvastatin sodium crystal form IX
Example 44
A 100 ml flask is charged with a solution of fluvastatin methyl ester (3.0 g), ethanol (7.5 ml), and NaOH (0.28 g) in water (0.75 ml). The mixture was heated to reflux for 2 hours, propan-2-ol (58 ml) was added and the mixture was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with propan-2-ol (50 ml), dried in a vacuum oven at 50 ° C. for 24 hours to obtain 1.92 g (62.8%) fluvastatin sodium crystal Form IX Got.

Example 45
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (75 ml) at reflux temperature. Dichloromethane (75 ml) was added dropwise to obtain a precipitate, and the mixture was stirred at reflux temperature for 2.5 hours. The suspension was cooled to room temperature and stirred at this temperature for 20 hours. The product was filtered, washed with dichloromethane (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.5 g (51%) of fluvastatin sodium crystalline Form IX.

Example 46
A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate (100 ml) was stirred at reflux temperature for 2.5 hours. The suspension was cooled to room temperature. The product was filtered, washed with ethyl acetate (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 2.0 g (66%) of fluvastatin sodium crystalline Form IX.

Example 47
Fluvastatin sodium crystal Form B (5.0 g) was almost completely dissolved in ethanol (100 ml) at 45 ° C. The solution was filtered and cooled to room temperature. Ethyl acetate (250 ml) was added and the mixture was stirred at room temperature for 63 hours to give a precipitate. The product was filtered under a stream of nitrogen, washed with ethyl acetate (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 2.2 g (44%) of fluvastatin sodium crystalline Form IX.

Example 48
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130 ml) at room temperature. The solution was filtered and diethyl ether (260 ml) was added. The mixture was stirred at room temperature for 16 hours to obtain a precipitate. The product was filtered and dried in a vacuum oven at 50 ° C. for 22 hours to give 1.7 g (56%) of fluvastatin sodium crystalline Form IX.

Example 49
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130 ml) at room temperature. The solution was filtered and n-pentane (260 ml) was added. The mixture was stirred at room temperature for 17 hours to obtain a precipitate. The product was filtered, washed with n-pentane (2 × 35 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.9 g (63%) fluvastatin sodium crystalline Form IX.

Example 50
Fluvastatin sodium crystal Form B (5.0 g) was almost completely dissolved in a mixture of ethanol (130 ml) and methanol (5 ml) at room temperature. The solution was filtered and hexane (200 ml) was added dropwise. The mixture was stirred at room temperature for 19 hours to obtain a precipitate. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 22 hours to give 3.6 g (73%) of fluvastatin sodium crystalline Form IX.

10) Preparation of fluvastatin sodium crystal form IX-1
Example 51
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. The solution was filtered and n-pentane (70 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for 1.5 hours. The product was filtered, washed with n-pentane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 2.2 g (73%) of fluvastatin sodium crystalline Form IX-1.

Example 52
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. The solution was filtered and diethyl ether (70 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for 0.5 hour. The mixture was cooled to room temperature. The product was filtered, washed with diethyl ether (2 × 5 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.0 g (65%) of fluvastatin sodium crystalline Form IX-1.

Example 53
A slurry of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate (240 ml) was heated to reflux temperature. Additional ethyl acetate (80 ml) was added at reflux temperature. The material recrystallized during reflux and the mixture was stirred at reflux temperature for 2.5 hours to give a large amount of precipitate. The mixture was cooled to room temperature. The product was filtered under a stream of nitrogen, washed with ethyl acetate (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 2.7 g (89%) of fluvastatin sodium crystalline Form IX-1. It was.

Example 54
A slurry of fluvastatin sodium crystal Form B (3.0 g) in isobutyl acetate (70 ml) was heated to reflux temperature. The material recrystallized during reflux and MTBE (70 ml) was added dropwise to obtain a large amount of precipitate. The mixture was stirred at reflux temperature for a further 0.5 hour. The mixture was cooled to room temperature. The product was filtered under a stream of nitrogen, washed with MTBE (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.74 g (91%) of fluvastatin sodium crystalline Form IX-1. .

Example 55
Fluvastatin sodium crystal Form B (3.0 g) was almost completely dissolved in isobutyl acetate (70 ml) at reflux temperature. Dichloromethane (70mnl) was added dropwise to obtain a precipitate. The mixture was cooled to room temperature. The product was filtered, washed with dichloromethane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 25 hours to give 2.5 g (82%) of fluvastatin sodium crystalline Form IX-1.

Example 56
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130 ml) at room temperature. The solution was filtered and hexane (200mnl) was added dropwise. The mixture was stirred at room temperature for 19 hours. The product was filtered under a stream of nitrogen, washed with hexane (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.2 g (41%) of amorphous fluvastatin sodium. After 20 days, a precipitate was observed in the mother liquor. The precipitate was dried in a vacuum oven at 50 ° C. for 26 hours to obtain fluvastatin sodium crystal Form IX-1.

Example 57
A slurry of fluvastatin sodium crystal Form B (3.0 g) in toluene (60 ml) and cyclohexane (60 ml) was heated to reflux for 22 hours. The mixture was cooled to room temperature. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.6 g (85%) of fluvastatin sodium crystalline Form IX-1.

Example 58
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (100 ml) at reflux temperature. The solution was filtered and hexane (100 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for 1 hour and then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with hexane (2 × 20 ml) and dried in a vacuum oven for 19 hours at 50 ° C. to give 2.5 g (83%) of fluvastatin sodium crystalline Form IX-1. .

Example 59
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (100 ml) at reflux temperature. The solution was filtered and MTBE (60 ml) was added dropwise at reflux temperature. The mixture was stirred at reflux temperature for 1 hour and then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with MTBE (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 18 hours to give 1.9 g (63%) of fluvastatin sodium crystalline Form IX-1. .

Example 60
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in MEK (70 ml) at reflux temperature. MTBE (70 ml) was added dropwise at reflux temperature. The mixture was cooled to room temperature. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 29 hours to give 0.7 g (24%) of fluvastatin sodium crystalline Form IX-1.

11) Preparation of fluvastatin sodium crystal form XI
Example 61
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallized. Hexane (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 4.5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with hexane (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 23.5 hours to give 2.8 g (93%) of fluvastatin sodium crystalline Form XI.

Example 62
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallized. N-Pentane (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 4 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with n-pentane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 23.5 hours to give 2.76 g (92%) of fluvastatin sodium crystalline Form XI .

Example 63
Fluvastatin sodium (3.0 g) was dissolved in butan-2-ol (70 ml) at reflux temperature. MTBE (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with MTBE (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 2.7 g (90%) fluvastatin sodium crystalline Form XI.

Example 64
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallized. Diethyl ether (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 4.5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with diethyl ether (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.8 g (94%) of fluvastatin sodium crystalline Form XI.

Example 65
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallized. N-Heptane (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 4.5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with n-heptane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.8 g (94%) of fluvastatin sodium crystalline Form XI .

Example 66
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml) at reflux temperature. During this time the material recrystallized. Chloroform (70 ml) was added at reflux temperature to obtain a large amount of precipitate. The resulting suspension was stirred at reflux temperature for 4 hours. The mixture was then cooled to room temperature. The product was isolated by filtration, washed with chloroform (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.7 g (94%) of fluvastatin sodium crystalline Form XI.

12) Preparation of fluvastatin sodium crystal form XI-2
Example 67
Fluvastatin sodium (3.0 g) was almost completely dissolved in propan-1-ol (60 ml) at reflux temperature. Hexane (60 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 1.5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with hexane (2 × 20 ml), dried in a vacuum oven at 50 ° C. for 28 hours, and 2.3 g (78%) of fluvastatin sodium crystal Form XI-2 Got.

Example 68
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux temperature. MTBE (60 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 40 minutes. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with MTBE (2 × 30 ml), dried in a vacuum oven at 50 ° C. for 28 hours to give 2.5 g (82%) fluvastatin sodium crystalline Form XI-2 Got.

Example 69
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux temperature. Dichloromethane (60 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for 30 minutes. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with dichloromethane (2 × 20 ml), dried in a vacuum oven at 50 ° C. for 24 hours to give 0.3 g (11%) of fluvastatin sodium crystal Form XI-2 Got.

13) Preparation of fluvastatin sodium crystal form XII
Example 70
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux temperature. 1,4-Dioxane (140 ml) was added in two portions at reflux temperature for 18 hours (2 × 70 ml). The cloudy solution was then cooled to room temperature and more 1,4-dioxane (70 ml) was added. The mixture was stirred at room temperature for 23 hours. Next, this was concentrated under reduced pressure and stirred at room temperature for 9.5 hours to obtain a precipitate. The product was filtered under a stream of nitrogen, washed with 1,4-dioxane (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 20 hours to obtain 0.35 g (12%) fluvastatin sodium crystalline Form XII. Obtained.

14) Preparation of fluvastatin sodium crystal form XIII
Example 71
A suspension of fluvastatin sodium crystal Form B (3.0 g) in acetonitrile (600 ml) was stirred at reflux temperature for 2 hours. The suspension was then cooled to 10 ° C. using an ice bath. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.1 g (70%) of fluvastatin sodium crystalline Form XIII.

15) Preparation of fluvastatin sodium crystal form XVI
Example 72
Fluvastatin sodium (3.0 g) was almost completely dissolved in propan-2-ol (70 ml) at reflux temperature. Dichloromethane (70 ml) was added dropwise at reflux temperature. The resulting solution was stirred at reflux temperature for 3 hours. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. The product was isolated by filtration, washed with dichloromethane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 1.3 g (44%) of fluvastatin sodium crystalline Form XVI.

16) Preparation of fluvastatin sodium crystal form XVII
Example 73
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux temperature. The resulting solution was stirred at reflux temperature for 3 hours. During this time, the material recrystallized. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with propan-1-ol (1 × 10 ml), dried in a vacuum oven at 50 ° C. for 21 hours, and 0.2 g (7%) of fluvastatin sodium crystals XVII type was obtained.

17) Preparation of fluvastatin sodium crystal form XVIII
Example 74
Fluvastatin sodium (3.0 g) was dissolved in MEK (30 ml) at reflux temperature for 16 hours. The solvent was then distilled off and the residue was dried in a vacuum oven for 24 hours, yielding 2.7 g (90%) of fluvastatin sodium crystalline Form XVIII.

Example 75
Fluvastatin sodium (3.0 g) was dissolved in MEK (30 ml) at reflux temperature for 2.5 hours. The mixture was then cooled to room temperature. The product was isolated by filtration under nitrogen, washed with MEK (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 25.5 hours to give 2.6 g (86%) of fluvastatin sodium crystalline Form XVIII It was.

18) Preparation of fluvastatin sodium crystal form XIX
Example 76
Fluvastatin sodium Form XI (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled at about 80% relative humidity for 11 days. Fluvastatin sodium type XIX was recovered.

Example 77
Fluvastatin sodium Form XI (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled to about 100% relative humidity for 11 days. Fluvastatin sodium type XIX was recovered.

Example 78
Fluvastatin sodium type IV-1 (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled to about 80% relative humidity for 11 days. Fluvastatin sodium type XIX was recovered.

Example 79
Fluvastatin sodium type IV-1 (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled to about 100% relative humidity for 11 days. Fluvastatin sodium type XIX was recovered.

Example 80
Fluvastatin sodium Form XVI (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled at about 80% relative humidity for 24 days. Fluvastatin sodium type XIX was recovered.

Example 81
Fluvastatin sodium form XVI (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled to about 100% relative humidity for 24 days. Fluvastatin sodium type XIX was recovered.

19) Preparation of fluvastatin sodium crystal form XIX-1
Example 82
Wet fluvastatin sodium crystal Form XI (10.0 g) was stirred with water (10 ml) at room temperature for 6 hours. The product was then filtered under a stream of nitrogen, washed with water (2 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to give 3.8 g of fluvastatin sodium crystal form XIX-1.

20) Preparation of fluvastatin sodium crystal form XX
Example 83
Fluvastatin sodium Form XVI (˜300 mg) was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled to about 80% relative humidity for 1 day. Fluvastatin sodium form XX was recovered.

21) Preparation of fluvastatin sodium crystal form XXII
Example 84
About 300 mg of fluvastatin sodium form XV was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled at about 100% relative humidity for 14 days to recover fluvastatin sodium form XXII.

22) Preparation of fluvastatin sodium crystal form XXIII
Example 85
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in propan-1-ol (100 ml) at reflux temperature. After 1 hour, the material recrystallized at reflux temperature. The suspension was stirred at reflux temperature for a further 2 hours. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours to obtain a large amount of precipitate. The product was filtered under a stream of nitrogen, washed with propan-1-ol (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 72 hours to obtain 3.3 g (66%) of fluvastatin sodium crystals form XXIII. Obtained.

23) Preparation of fluvastatin sodium crystal form XXIV
Example 86
Fluvastatin sodium crystal form XV (5.0 g) was dissolved in water (14 ml) at reflux temperature. The mixture was stirred at reflux temperature for 1.5 hours and then cooled to room temperature. The mixture was stirred at room temperature for 16 hours to obtain a large amount of precipitate. The product was filtered under a stream of nitrogen, washed with water (2 × 3 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 4.5 g (90%) of fluvastatin sodium crystals Form XXIV.

Example 87
Fluvastatin sodium crystal form XV (5.0 g) was dissolved in water (9 ml) at reflux temperature. The mixture was stirred at reflux temperature for 1.5 hours and then cooled to room temperature. The mixture was stirred at room temperature for 16 hours to obtain a large amount of precipitate. The product was filtered under a stream of nitrogen, washed with water (1 × 5 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.2 g (84%) of fluvastatin sodium crystals Form XXIV.

Example 88
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (5 ml) at reflux temperature. The mixture was stirred at reflux temperature for 2 hours and then cooled to room temperature. The product was dried in a vacuum oven at 50 ° C. for 24 hours (no filtration) to give 4.4 g (88%) of fluvastatin sodium crystals Form XXIV.

Example 89
A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml) was stirred at room temperature for 1 hour. Diethyl ether (100 ml) was added and the mixture was stirred for 5 minutes. The organic and aqueous phases were separated. Traces of diethyl ether were removed from the aqueous phase under reduced pressure. The aqueous solution was lyophilized for 72 hours to obtain fluvastatin sodium crystal form XXIV.

Example 90
A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml) was stirred at room temperature for 1 hour. Diethyl ether (100 ml) was added and the mixture was stirred for 15 minutes. The organic and aqueous phases were separated. Traces of diethyl ether were removed from the aqueous phase under reduced pressure. The aqueous solution was lyophilized for 96 hours to obtain fluvastatin sodium crystal form XXIV.

24) Preparation of fluvastatin sodium crystal XXVI type
Example 91
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (20 ml) and water (1 ml) at reflux temperature. The solution was stirred at reflux temperature for 1 hour. The mixture was then cooled to room temperature and stirred at this temperature for 1.5 hours to obtain a large amount of precipitate. The product was dried in a vacuum oven at 50 ° C. for 22 hours (no isolation by filtration) to give 3.2 g (107%) of fluvastatin sodium crystals Form XXVI.

25) Preparation of fluvastatin sodium crystal form XXVII
Example 92
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (20 ml) and water (1 ml) at reflux temperature. Hexane (30 ml) was added dropwise at reflux temperature and the resulting mixture was stirred at this temperature for an additional hour. The mixture was then cooled to room temperature and stirred at this temperature for 1 hour to obtain a large amount of precipitate. The product was isolated by filtration, washed with hexane (3 × 20 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.5 g (82%) of fluvastatin sodium crystals Form XXVII.

26) Preparation of fluvastatin sodium crystal form XXIX
Example 93
Fluvastatin sodium crystal form XV (5.0 g) was stirred in refluxing temperature for 16 hours in 1,4-dioxane (80 ml). The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with 1,4-dioxane (4 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to obtain 3.8 g (76%) of fluvastatin sodium crystals form XXIX. Obtained.

27) Preparation of fluvastatin sodium crystal form XXX
Example 94
Fluvastatin sodium crystal form XV (5.0 g) was stirred at reflux temperature in methyl ethyl ketone (MEK) (70 ml) for 16 hours. The suspension was then cooled to room temperature. The product was isolated by filtration under a stream of nitrogen, washed with MEK (4 × 15 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 4.2 g (84%) of fluvastatin sodium crystal form XXX It was.

Example 95
Fluvastatin sodium crystal form XV (5.0 g) was stirred at reflux temperature in tetrahydrofuran (THF) (50 ml) for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with THF (2 × 15 ml), and dried in a vacuum oven at 50 ° C. for 21 hours to give 3.9 g (78%) of fluvastatin sodium crystal form XXX.

Example 96
Fluvastatin sodium crystal form XV (5.0 g) was stirred in acetone (75 ml) at reflux temperature for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with acetone (3 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.0 g (80%) of fluvastatin sodium crystal form XXX.

Example 97
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in butan-2-ol (60 ml) at reflux temperature for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with butan-2-ol (3 × 25 ml) and dried in a vacuum oven at 50 ° C. for 25 hours to give 4.2 g (84%) of fluvastatin sodium crystals form XXX. Obtained.

Example 98
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in butan-1-ol (60 ml) at reflux temperature for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with butan-2-ol (4 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.2 g (84%) of fluvastatin sodium crystals form XXX. Obtained.

Example 99
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 65 ° C. for 3.5 hours. Then more NaOH (0.5 eq) in water (0.4 ml) was added. After an additional 40 minutes, starting material was no longer detected by HPLC. Acetone (58 ml) was added dropwise to the solution over 25 minutes. Turbidity appeared in the solution. The mixture was slowly cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.25 g (8.2%) of fluvastatin sodium crystalline Form XXX.

28) Preparation of fluvastatin sodium crystals XXXI type
Example 100
Fluvastatin sodium crystal form XV (5.0 g) was stirred in ethanol (100 ml) at reflux temperature for 23 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with ethanol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 4.4 g (88%) of fluvastatin sodium crystals Form XXXI.

29) Preparation of fluvastatin sodium crystals XXXIII type
Example 101
Fluvastatin sodium crystal form XV (5.0 g) was stirred in refluxing temperature for 16 hours in absolute ethanol (40 ml). The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with absolute ethanol (4 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.2 g (84%) of fluvastatin sodium crystals Form XXXIII.

Example 102
Absolute ethanol was added to fluvastatin sodium form B (5.0 g) in four portions (1 × 60 ml, 3 × 20 ml). The heterogeneous mixture was stirred at reflux temperature for 1.25 hours. The suspension was then cooled to room temperature and stirred at this temperature for 23 hours. The product was filtered under a stream of nitrogen, washed with absolute ethanol (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.3 g (45%) of fluvastatin sodium crystals form XXXIII.

Example 103
Absolute ethanol was added to fluvastatin sodium form B (5.0 g) in two portions (2 × 100 ml). The heterogeneous mixture was stirred at reflux temperature for 3 hours. The suspension was then cooled to room temperature and stirred at this temperature for 18 hours. The product was filtered under a stream of nitrogen, washed with absolute ethanol (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.8 g (16%) of fluvastatin sodium crystals Form XXXIII.

30) Preparation of fluvastatin sodium crystals XXXIV type
Example 104
Fluvastatin sodium crystal form XV (5.0 g) was stirred in DMSO (50 ml) at 100 ° C. for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with DMSO (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.6 g (71%) fluvastatin sodium crystals form XXXIV.

31) Preparation of fluvastatin sodium crystals XXXV type
Example 105
Fluvastatin sodium crystal form XV (5.0 g) was stirred in DMF (50 ml) at 95 ° C. for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with DMF (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.9 g (984%) of fluvastatin sodium crystals form XXXV.

32) Preparation of fluvastatin sodium crystals XXXVI type
Example 106
Fluvastatin sodium crystal XIV wet form (10.0 g) in water (10 ml) was stirred at room temperature for 6 hours. The product was then filtered under a stream of nitrogen and washed with water (1 × 2 ml) to give 9.6 g (88%) of fluvastatin sodium crystals Form XXXVI.

33) Preparation of fluvastatin sodium crystals XXXVII type
Example 107
Fluvastatin sodium form XI (6.0 g) in water (12 ml) was stirred at room temperature for 5.75 hours. The product was then filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 23 hours to give 4.1 g (68%) of fluvastatin sodium crystals Form XXXVII.

34) Preparation of fluvastatin sodium crystal form XXXVIII
Example 108
Fluvastatin sodium Form XI (2.5 g) was suspended in absolute ethanol (13.5 ml) at reflux temperature for 16 hours. The suspension was then cooled to room temperature and stirred at this temperature for 3 hours. The product was filtered under a stream of nitrogen, washed with absolute ethanol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 2.0 g (79%) of fluvastatin sodium crystals form XXXVIII.

Example 109
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq) in ethanol (15 ml). The mixture was stirred at about 70 ° C. for 4 hours (clarified and replaced with a slurry) and then no starting material was detected by HPLC. Then 40 ml of ethyl acetate was added dropwise to the mixture, cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with ethyl acetate (10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium crystals form XXXVIII (1.78 g, 87.4%) .

Example 110
Fluvastatin sodium form XI (2.5 g) was suspended in absolute ethanol (13.5 ml) at reflux temperature. The suspension was then cooled to room temperature and stirred at this temperature for 3 hours. The product was filtered under a stream of nitrogen, washed with absolute ethanol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 2.0 g (79%) of fluvastatin sodium crystals form XXXVIII.

35) Preparation of fluvastatin sodium crystal XXXIX type
Example 111
A 100 ml flask is charged with a solution of fluvastatin methyl ester (2.0 g), NaOH (0.19 g) in ethanol (5 ml). The mixture was refluxed for 3.5 hours and propan-2-ol (40 ml) was added. The slurry was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with propan-2-ol (20 ml), dried in a vacuum oven at 50 ° C. for 24 hours to obtain 1.93 g (95%) of fluvastatin sodium crystals form XXXIX Got.

36) Preparation of fluvastatin sodium crystal XLI type
Example 112
Fluvastatin sodium form XV (6.0 g) was dissolved in water (16 ml) at reflux temperature. Acetonitrile (60 ml) was added dropwise and the mixture was stirred at reflux for 1 hour. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. Further acetonitrile (70 ml) was added to obtain a precipitate. After 3.5 hours, the product was isolated by filtration under nitrogen, washed with acetonitrile (2 × 20 ml), dried in a vacuum oven at 50 ° C. for 25 hours, and 2.96 g (49%) of fluvastatin sodium crystals Obtained XLI type.

37) Preparation of fluvastatin sodium crystal XLII form
Example 113
Fluvastatin (3.0 g) was completely dissolved in MEK (40 ml) at room temperature. The solution was filtered to give a clear solution and 97% NaOH (0.29 g) dissolved in methanol (3 ml) was added to this solution. The solution was stirred at room temperature for 94 hours to obtain a gelatinous precipitate. The product was filtered under a stream of nitrogen, washed with MEK (2 × 11 ml) and dried in a vacuum oven at 50 ° C. for 25.5 hours to give 2.6 g (85.5%) of fluvastatin sodium crystalline form XLII.

Example 114
Fluvastatin (2.0 g) was completely dissolved in methanol (5 ml) at reflux temperature and NaOH (0.19 g) was added. The solution was stirred at reflux temperature for 3 hours to obtain a precipitate having a pasty viscosity. Ethyl acetate (40 ml) was added at reflux temperature, then the solution was cooled to room temperature and the slurry was stirred for 3 hours. The product was filtered under a stream of nitrogen, washed with ethyl acetate (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 1.58 g (77.5%) of fluvastatin sodium crystalline form XLII.

Example 115
Fluvastatin (3.0 g) was completely dissolved in dichloromethane (35 ml) at room temperature and the solution was filtered to obtain a clear solution. NaOH (0.29 g) dissolved in methanol (3 ml) was added to the solution, then the solution was stirred at room temperature for 23 hours to obtain a precipitate. The product was filtered under a stream of nitrogen, washed with dichloromethane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 42 hours to give 2.3 g (75%) of fluvastatin sodium crystalline form XLII.

Example 116
Fluvastatin (3.0 g) was completely dissolved in dichloromethane (35 ml) at room temperature and the solution was filtered to obtain a clear solution. NaOH (0.29 g) dissolved in ethanol (5 ml) was added to the solution and then the solution was stirred at room temperature for 23 hours to obtain a precipitate. The product was filtered under a stream of nitrogen, washed with dichloromethane (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 42 hours to give 1.88 g (61.5%) fluvastatin sodium crystalline form XLII.

38) Preparation of fluvastatin sodium crystal XLIII type
Example 117
Fluvastatin sodium Form B (5.0 g) was dissolved in water (15 ml) at reflux temperature. Propan-2-ol (45 ml) was added dropwise and the mixture was stirred at reflux for 2 hours. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. Further, propan-2-ol (50 ml) was added to obtain a large amount of precipitate. After 7.5 hours, the product was isolated by filtration under nitrogen, washed with propan-2-ol (2 × 25 ml), dried in a vacuum oven at 50 ° C. for 24 hours, 0.74 g (15%) Fluvastatin sodium crystal XLIII type was obtained.

Example 118
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq). The mixture was stirred at about 70 ° C. for 2 hours until no material was observed by HPLC. After this time propan-2-ol (10 ml) was added dropwise and the solution was slowly cooled to room temperature. An additional 40 ml of propan-2-ol (in 3 times) was added to the solution at room temperature, but no precipitate formed. The solution was stirred overnight and a gel-like precipitate formed. The mixture was heated to reflux to dissolve the gel. The mixture was then cooled to room temperature. A yellow slurry was obtained. After stirring overnight, an additional 15 ml of propan-2-ol was added. The product was isolated by filtration under nitrogen, washed with propan-2-ol (25 ml), dried in a vacuum oven at 50 ° C. for 24 hours to give 0.46 g (22.6%) fluvastatin sodium crystalline form XLIII Got.

39) Preparation of fluvastatin sodium crystal XLIV type
Example 119
Amorphous fluvastatin sodium (1.5 g) was suspended in propan-2-ol (31 ml) at reflux temperature for 4.25 hours. The suspension was then cooled to room temperature and stirred at this temperature for 1 hour. The product was filtered under a stream of nitrogen, washed with propan-2-ol (2 × 35 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to obtain 0.4 g (25%) of fluvastatin sodium crystalline form XLIV. Obtained.

Example 120
Fluvastatin methyl ester (3.0 g) was added to acetone (30 ml) and the solution was stirred at room temperature. NaOH (1 eq) in ethanol (3 ml) was added to the solution. The mixture was stirred overnight. The precipitated product was isolated by filtration under nitrogen, washed with acetone (100 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to obtain 2.45 g (80.8%) of fluvastatin sodium crystalline form XLIV. It was.

40) Preparation of fluvastatin sodium crystal XLV type
Example 121
A suspension of fluvastatin sodium Aml form (2.6 g) in propan-2-ol (36 ml) was stirred at room temperature. The product was then filtered under a stream of nitrogen, washed with propan-2-ol (2 × 20 ml), dried in a vacuum oven at 50 ° C. for 20.5 hours, and 2.4 g (92%) of fluvastatin sodium crystals XLV Got the mold.

Preparation of Aml type Fluvastatin-diol-methyl ester (FDME) (3.0 g) was added to cyclohexane (60 ml) and the mixture was heated to reflux. When NaOH (1 eq) dissolved in methanol (3 ml) was added to the slurry solution, the solution became clear. A precipitate appeared after 15 minutes. After another hour the mixture was cooled to room temperature and cyclohexane (40 ml) was added and this was stirred overnight. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.73 g (90%) fluvastatin sodium Aml.

41) Preparation of fluvastatin sodium crystal XLVI type
Example 122
A 100 ml flask was charged with a solution of fluvastatin methyl ester (2.42 g), ethanol (5 ml), and NaOH (0.23 g) in ethanol (7 ml). The mixture was stirred at reflux temperature for 2.5 hours and acetonitrile (50 ml) was added. The slurry was stirred at reflux temperature for a further 3 hours, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.02 g (83%) of fluvastatin sodium crystalline form XLVI.

42) Preparation of fluvastatin sodium crystal XLVII type
Example 123
About 300 mg of fluvastatin sodium form XVIII was placed on a flat dish with a diameter of 35 mm and placed in a chamber controlled at about 80% relative humidity for 25 days to recover fluvastatin sodium form XLVII.

43) Preparation of fluvastatin sodium crystal XLVIII type
Example 124
Fluvastatin methyl ester (3.0 g) and NaOH (1 equivalent) dissolved in methanol (7.5 ml) were added to a three-necked flask. The mixture was refluxed for 6.5 hours. Next, acetonitrile (50 ml) was added dropwise to the refluxing solution over 10 minutes. The mixture was then cooled to room temperature and stirred for 46 hours. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.84 g (60.7%) of fluvastatin sodium XLVIII form.

Example 125
Fluvastatin sodium type B (5.0 g) was stirred under reflux in methanol (40 ml) for 5 hours. The slurry was cooled to room temperature and stirred at room temperature for 17 hours. The product was filtered under a stream of nitrogen, washed with methanol (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to give 0.28 g (5.6%) fluvastatin sodium XLVIII form.

Example 126
Fluvastatin sodium Form B (5.0 g) was dissolved in methanol (24 ml) at room temperature. The solution was heated to reflux to obtain a precipitate. The resulting slurry was cooled to room temperature and stirred at room temperature for 19.5 hours. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.53 g (10.6%) of fluvastatin sodium XLVIII form.

Example 127
Fluvastatin (3.0 g) was completely dissolved in methanol (15 ml) at reflux temperature. The solution was then filtered to obtain a clear solution and heated to reflux again. NaOH (0.29 g) was added at reflux temperature to obtain a precipitate. The slurry was cooled to room temperature to obtain a pasty mixture. Acetone (30 g) was added dropwise at room temperature, and the solution was stirred at room temperature for 21 hours to obtain a large amount of precipitate. The product was filtered under a stream of nitrogen, washed with acetone (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 1.89 g (62%) of fluvastatin sodium XLVIII form.

44) Preparation of fluvastatin sodium crystal XLIX type
Example 128
Fluvastatin type B (5.0 g) was dissolved in methanol (40 ml) at room temperature. The solution was heated to reflux temperature and MTBE (100 ml) was added dropwise to obtain a precipitate. The resulting suspension was stirred at reflux temperature for 1 hour. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under a stream of nitrogen, washed with MTBE (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.2 g (64%) of fluvastatin sodium crystalline form XLIX.

45) Preparation of fluvastatin sodium crystal form L
Example 129
Fluvastatin sodium (5.0 g) was dissolved in methanol (35 ml) at room temperature. The solution was heated to reflux and a precipitate was obtained during the addition of ethyl acetate added dropwise with ethyl acetate (100 ml). The mixture was stirred at reflux temperature for 1.5 hours. The suspension was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.7 g (14%) of fluvastatin sodium Form L.

46) Preparation of fluvastatin sodium crystalline form LI
Example 130
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in methanol (50 ml) at room temperature. The solution was heated to reflux temperature and acetonitrile (100 ml) was added dropwise to obtain a precipitate. The resulting suspension was stirred at reflux temperature for 1 hour. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under a stream of nitrogen, washed with acetonitrile (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 0.73 g (15%) fluvastatin sodium crystalline Form LI.

47) Preparation of fluvastatin sodium crystalline form LIII
Example 131
Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol (112 ml) at room temperature. The solution was heated to reflux temperature and ethyl acetate (320 ml) was added dropwise to give a precipitate. The resulting suspension was stirred at reflux temperature for 1.5 hours. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under a stream of nitrogen, washed with ethyl acetate (1 × 25 ml) and dried in a vacuum oven at 50 ° C. for 23.5 hours to give 2.1 g (13%) of fluvastatin sodium crystalline Form LIII.

48) Preparation of fluvastatin sodium crystalline LIV form
Example 132
Fluvastatin (3.52 g) was stirred with a solution of water (9.9 ml) and NaOH (0.32 g) at room temperature to obtain a mud suspension. The suspension was stirred overnight at room temperature. The product was filtered under a stream of nitrogen, washed with water (2 × 3 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.36 g (65.8%) of fluvastatin sodium form LIV.

49) Preparation of fluvastatin sodium crystal form LV
Example 133
Fluvastatin methyl ester (3.0 g) was added to acetone (60 ml) and the mixture was heated to reflux to dissolve. The solution was then cooled to about 40 ° C. and NaOH (1 eq) dissolved in methanol (7.5 ml) was added. Turbidity appeared immediately. After 30 minutes, an oil residue separated from the mixture. The mixture was again heated to about 55 ° C. for 3 hours to dissolve the oil. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.48 g (81.1%) of fluvastatin sodium LV form.

50) Preparation of fluvastatin sodium crystal LVI type
Example 134
A 250 ml flask was charged with fluvastatin-acetonide-methyl ester (4.4 g), THF (44 ml), and 1.5% HCl solution (0.67 ml). The mixture was stirred at room temperature for 10 hours, then NaOH (0.25 g) was added and the solvent was distilled off. The residue was dissolved in acetone (80 ml), NaOH (0.43 g) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washed with acetone (50 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.37 g of fluvastatin sodium crystalline form LVI.

51) Preparation of fluvastatin sodium crystal form LVII
Example 135
Fluvastatin sodium Form VII (20.5 g) was suspended in absolute ethanol (246 ml) at room temperature for 21 hours. The product was then filtered under nitrogen, washed with absolute ethanol (2 × 40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 11.8 g (58%) of fluvastatin sodium form LVII. .

52) Preparation of fluvastatin sodium crystalline form LVIII
Example 136
Propan-2-ol (120 ml) was heated to reflux temperature. Fluvastatin sodium (5.0 g) was added to the boiling solvent. The mixture was stirred at reflux temperature for 3 hours. The suspension was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under nitrogen, washed with propan-2-ol (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to obtain 4.7 g (95%) of fluvastatin sodium Form LVIII It was.

53) Preparation of fluvastatin sodium crystalline form LX
Example 137
Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol (112 ml) at room temperature. The solution was heated to reflux temperature and ethyl acetate (320 ml) was added dropwise to give a precipitate. The resulting suspension was stirred at reflux temperature for 1.5 hours. The mixture was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under nitrogen, washed with ethyl acetate (1 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.3 g (14%) of fluvastatin sodium crystalline form LX.

54) Preparation of fluvastatin sodium crystal LXIV type
Example 138
A three-necked flask was charged with fluvastatin methyl ester (3.0 g) and methanol (30 ml). The mixture was heated to reflux to dissolve and NaOH (0.42) was added in two portions. A precipitate appeared at reflux temperature and did not dissolve until an additional 45 ml of methanol was added for 4 hours. The slurry mixture was cooled to room temperature and stirred overnight. The precipitate was dissolved, acetone (150 ml) was added and the mixture was stirred at room temperature for 22 hours. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 1.68 g of fluvastatin sodium crystalline form LXIV.

Example 139
Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) and filtered. A solution of NaOH (1.46 g) in methanol (15 ml) was added and the solution was stirred at room temperature. After 2 hours a solution of NaOH (0.73 g) in methanol (15 ml) was added and the mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone, and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium form LXIV.

Example 140
Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) and filtered. A solution of NaOH (1.46 g) in methanol (15 ml) was added and the solution was stirred at room temperature. After 2 hours a solution of NaOH (0.73 g) in methanol (15 ml) was added. After 2 hours the mixture was cooled to 14 ° C. and stirred at this temperature overnight. The product was isolated by filtration under nitrogen, washed with acetone, and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium form LXIV.

55) Preparation of fluvastatin sodium crystal LXV type
Example 141
A 100 ml flask was charged with fluvastatin methyl ester (3.0 g), methanol (20 ml) and NaOH (0.29 g). After a clear solution was obtained, propan-2-ol (80 ml) was added and the solution was stirred at room temperature overnight. A slight precipitate appeared, propan-2-ol (40 ml) was added and the solution was stirred overnight at room temperature. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 0.92 g of fluvastatin sodium crystalline form LXV.

Example 142
Fluvastatin methyl ester (3.0 g) was dissolved in methanol (15 ml) by heating under reflux. NaOH (0.29 g) was added and the clear solution was stirred at reflux for 30 minutes, then acetone (75 ml) was added. The solution was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to give 1.34 g of fluvastatin sodium crystalline form LXV.

56) Preparation of fluvastatin sodium crystal LXVI type
Example 143
A 50 ml flask was charged with fluvastatin sodium crystals Form VI (1.98 g) and water (4 ml), and the mixture was then heated to reflux to dissolve. After 2 hours, the solution was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with water (3 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.25 g (63%) of fluvastatin sodium crystalline form LXVI.

Example 144
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (10 ml) at reflux temperature. The solution was stirred at reflux temperature for 2 hours. The solution was then cooled to room temperature and stirred at this temperature for 16 hours to obtain a precipitate. The product was filtered under a stream of nitrogen, washed with water (2 × 2 ml) and dried in a vacuum oven at 50 ° C. for 24.5 hours to give 4.4 g (89%) of fluvastatin sodium crystalline form LXVI.

Example 145
Fluvastatin sodium crystal form XV (5.0 g) was dissolved in water (14 ml) at reflux temperature. The solution was stirred at reflux temperature for 1.25 hours. The solution was then cooled to room temperature and stirred at this temperature for 16 hours to obtain a precipitate. The product was filtered under a stream of nitrogen, washed with water (2 × 3 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 4.2 g (84%) of fluvastatin sodium crystalline form LXVI.

57) Preparation of fluvastatin sodium crystal form LXVII
Example 146
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and a solution of NaOH (0.36 g) in methanol (5 ml) was added. After 3 hours NaOH (0.072 g) was added and the mixture was stirred at room temperature for an additional 21 hours. NaOH (0.073 g) was added and the mixture was stirred for an additional 4 hours. The product was isolated by filtration under nitrogen, washed with acetone (55 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.64 g of fluvastatin sodium crystalline Form LXVII.

Example 147
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), a solution of NaOH (0.58 g) in methanol (8 ml) was added and the mixture was stirred at room temperature for an additional 3.75 hours. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 2.54 g of fluvastatin sodium crystalline form LXVII.

Example 148
Fluvastatin methyl ester (10.0 g) was dissolved in acetone (150 ml) and a solution of NaOH (0.94 g) in methanol (10 ml) was added. After 26.5 hours, NaOH (0.47 g) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 8.01 g of fluvastatin sodium crystalline form LXVII.

58) Preparation of fluvastatin sodium crystalline form LVIII
Example 149
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and a solution of NaOH (0.44 g) in methanol (6 ml) was added. After 29 hours, NaOH (0.14 g) was added and the mixture was stirred at room temperature for an additional hour, which was cooled in an ice bath for 30 minutes. The product was isolated by filtration under nitrogen, washed with acetone (38 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 2.76 g of fluvastatin sodium crystalline form LXVIII.

Example 150
Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml), a solution of NaOH (1.46 g) in methanol (15 ml) was added and the solution was stirred at room temperature. After 27 hours, NaOH (0.73 g) in methanol (15 ml) was added and the mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone and dried in a vacuum oven at 50 ° C. for 24 hours to give fluvastatin sodium form LXVIII.

59) Preparation of fluvastatin sodium crystal LXIX type
Example 151
A 50 ml flask was charged with fluvastatin sodium crystals Form VI (1.63 g) and propan-2-ol (28 ml) and then the mixture was heated to reflux. After 2 hours, propan-2-ol (4 ml) was added and the slurry was stirred at reflux for an additional 20 minutes, cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with propan-2-ol (30 ml), dried in a vacuum oven at 50 ° C. for 24 hours to give 1.52 g (93%) fluvastatin sodium crystalline form LXIX Got.

60) Preparation of fluvastatin sodium crystal LXX type
Example 152
Fluvastatin sodium crystal LXVII type (2.0 g) and water (3.4 ml) were placed in a 100 ml flask. The mixture was dissolved by heating to reflux and acetone (34 ml) was added. After 2 hours, the mixture was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.69 g (84.5%) fluvastatin sodium crystalline form LXX.

61) Preparation of fluvastatin sodium crystal LXXI type
Example 153
A 100 ml flask was charged with fluvastatin sodium crystals LXVII type (2.0 g) and water (2 ml). The mixture was heated to reflux and acetone (74 ml) was added. After 2 hours, the mixture was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.85 g (92.5%) fluvastatin sodium crystalline form LXXI.

62) Preparation of fluvastatin sodium crystal form LXXII
Example 154
A 100 ml flask was charged with fluvastatin sodium crystals Form VI (1.33 g), acetone (28 ml), and water (0.7 ml). The mixture was heated to reflux for 2 hours, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.26 g (95%) fluvastatin sodium crystalline form LXXII.

Example 155
A 100 ml flask was charged with fluvastatin sodium crystals Form VI (1.12 g) and acetonitrile (19 ml). The mixture was heated to reflux for 2 hours, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.02 g (86%) fluvastatin sodium crystalline form LXXII.

63) Preparation of fluvastatin sodium crystal form LXXIV
Example 156
A suspension of fluvastatin sodium crystals Form B (30.0 g) in a mixture of propan-2-ol (501 ml) and water (51 ml) was heated to reflux for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with propan-2-ol (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to obtain 4.7 g (16%) of fluvastatin sodium crystalline form LXXIV. Obtained.

Example 157
A suspension of fluvastatin sodium crystal Form B (2.0 g) in a mixture of propan-2-ol (33.3 ml) and water (4.3 ml) was heated to reflux for 4 hours. The suspension was then cooled in an ice bath. The product was filtered under a stream of nitrogen, washed with propan-2-ol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 17.5 hours to obtain 0.4 g (20%) of fluvastatin sodium crystalline form LXXIV. Obtained.

64) Preparation of fluvastatin sodium crystal LXXV type
Example 158
Fluvastatin sodium crystal XXX type (2.0 g) was refluxed in methanol (10 ml) for 15 hours, cooled to room temperature, and further stirred for 2 hours. The product was isolated by filtration under nitrogen, washed with methanol (15 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.48 g (24%) of fluvastatin sodium crystalline form LXXV.

64) Preparation of fluvastatin sodium crystal LXXVI type
Example 159
A 250 round bottom flask was charged with fluvastatin methyl ester (12.0 g), ethanol (60 ml), water (36 ml), and NaOH (1 eq). After 2 hours, ethanol was distilled off and the residue was divided into 4 fractions. Water was added (up to 20 times the amount) and extracted twice with ethyl acetate. The product was isolated by distillation of water to give wet fluvastatin sodium crystalline form LXXVI (sample stored at room temperature for 3 days).

66) Preparation of fluvastatin sodium crystal form LXXVII
Example 160
Fluvastatin methyl ester (3.0 g) was dissolved in ethyl acetate (90 ml), a solution of NaOH (0.2 g) in water (1 ml) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washed with ethyl acetate (50 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.52 g (49.7%) fluvastatin sodium crystalline form LXXVII. .

67) Preparation of fluvastatin sodium crystal LXXVIII
Example 161
A 100 ml round bottom flask was charged with fluvastatin methyl ester (4.0 g, 9.4 mmol), water (32 ml), and NaOH (0.39 g). The mixture was stirred at room temperature for 3 days and then extracted with ethyl acetate (32 ml, 16 ml). The aqueous solution was evaporated, propan-2-ol (40 ml) was added and the mixture was stirred at room temperature overnight. The mixture was scratched with a spatula and further stirred for 1 day to produce a precipitate. The product was isolated by filtration under a stream of nitrogen, washed with propan-2-ol (20 ml), dried in a vacuum oven at 50 ° C. for 24 hours to obtain 1.28 g (31%) fluvastatin sodium crystalline form LXXVIII Got.

Example 162
A 100 ml round bottom flask was charged with fluvastatin methyl ester (3.0 g, 7.08 mmol), water (30 ml), and NaOH (0.29 g). The mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate (30 ml). The aqueous solution was evaporated, acetonitrile (12 ml) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under a stream of nitrogen, washed with acetonitrile (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.37 g (12%) fluvastatin sodium crystalline form LXXVIII.

68) Preparation of fluvastatin sodium form XC
Example 163
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (140 ml). The resulting solution was filtered and cyclohexane (2 × 140 ml) was added in two portions. The mixture was stirred at room temperature for 26 hours to obtain a large amount of precipitate. The product was then filtered, washed with cyclohexane (2 × 25 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to give 1.7 g (55%) of fluvastatin sodium Form XC.

69) Preparation of fluvastatin sodium XCI type
Example 164
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in ethyl acetate (75 ml) was stirred at reflux temperature for 16 hours. The suspension was then cooled to room temperature. The product was filtered under a stream of nitrogen, washed with ethyl acetate (4 × 25 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 3.9 g (78%) of fluvastatin sodium Form XCI.

70) Preparation of fluvastatin sodium form XCII
Example 165
Fluvastatin sodium crystal Form B (1.0 g) was dissolved in ethanol (10 ml) and methanol (1 ml) at reflux temperature. Hexane (10 ml) was added in one portion and the cloudy solution was stirred at reflux for 4 hours. During this time a precipitate was obtained. The suspension was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under a stream of nitrogen, washed with hexane (3 × 7 ml) and dried in a vacuum oven at 50 ° C. for 19 hours to give 0.67 g (67%) fluvastatin sodium Form XCII.

71) Preparation of fluvastatin sodium form XCIII
Example 166
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in propan-1-ol (50 ml) was stirred at room temperature for 25 hours. The product was filtered under a stream of nitrogen, washed with propan-1-ol (3 × 40 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.8 g (76%) of fluvastatin sodium Form XCIII It was.

72) Preparation of fluvastatin sodium XCIV type
Example 167
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in butan-1-ol (50 ml) was stirred at room temperature for 24 hours. The product was filtered under a stream of nitrogen, washed with butan-1-ol (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to obtain 6.0 g (120%) of fluvastatin sodium Form XCIV It was.

73) Preparation of fluvastatin sodium XCV type
Example 168
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in ethyl acetate (90 ml) was stirred at room temperature for 19 hours. The product was filtered under a stream of nitrogen, washed with ethyl acetate (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 22 hours to give 5.2 g (104%) of fluvastatin sodium Form XCV.

Example 169
A suspension of fluvastatin sodium crystal form XV (5.0 g) in acetone (70 ml) was stirred at room temperature for 23 hours. The product was filtered under a stream of nitrogen, washed with acetone (2 × 15 ml) and dried in a vacuum oven at 50 ° C. for 20 hours to give 4.6 g (92%) of fluvastatin sodium form XCV.

Example 170
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in 1,4-dioxane (50 ml) was stirred at room temperature for 24 hours. The product is filtered under a stream of nitrogen, washed with 1,4-dioxane (2 × 30 ml) and dried in a vacuum oven at 50 ° C. for 23 hours to give 4.4 g (88%) of fluvastatin sodium form XCV. It was.

Example 171
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in MEK (70 ml) was stirred at room temperature for 30 hours. The product was filtered under a stream of nitrogen, washed with MEK (2 × 20 ml) and dried in a vacuum oven at 50 ° C. for 21 hours to give 4.7 g (93%) of fluvastatin sodium Form XCV.

74) Preparation of fluvastatin sodium XCVI type
Example 172
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in THF (70 ml) was stirred at room temperature for 29 hours. The product was then filtered under a stream of nitrogen, washed with THF (2 × 20 ml) and dried in a vacuum oven for 20 hours at 50 ° C. to give 4.1 g (82%) of fluvastatin sodium form XCVI. .

75) Preparation of fluvastatin sodium XCVII type
Example 173
A three-necked flask was charged with fluvastatin methyl ester (3.0 g) and cyclohexane (60 ml), and then the mixture was heated to reflux. A solution of NaOH (0.29 g) in methanol (3 ml) was added and the mixture was stirred at reflux for 1.6 hours. The slurry was cooled to room temperature, cyclohexane (40 ml) was added and the mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.81 g (93%) of fluvastatin sodium Form XCVII.

76) Preparation of fluvastatin sodium form XCVIII
Example 174
Fluvastatin methyl ester (3.0 g) was dissolved by heating at reflux in a solution of NaOH (0.29 g) in methanol (7.5 ml). The clear solution was stirred at reflux for 85 minutes and acetonitrile (50 ml) was added. The solution was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried in a vacuum oven at 50 ° C. for 25.5 hours to give 0.97 g of fluvastatin sodium Form XCVIII.

77) Preparation of fluvastatin sodium XCIX type
Example 175
A 50 ml flask was charged with fluvastatin sodium crystals Form VI (1.02 g) and ethanol (10 ml). After 2.5 hours ethanol (15 ml) was added and the mixture was stirred overnight at room temperature. The product was isolated by filtration under nitrogen, washed with ethanol (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 0.14 g (14%) fluvastatin sodium form XCIX.

78) Preparation of fluvastatin sodium form C
Example 176
Fluvastatin methyl ester (3.0 g) was dissolved in dichloromethane (35 ml). NaOH (0.29 g) was added and the mixture was stirred overnight at room temperature. The product was isolated by filtration under nitrogen, washed with dichloromethane (20 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.89 g (62%) of fluvastatin sodium Form C.

79) Preparation of fluvastatin sodium type CI
Example 177
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), NaOH (0.29 g) in methanol (8 ml) was added and the mixture was stirred at room temperature for a further 3.5 hours. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 2.37 g of fluvastatin sodium Form CI.

Example 178
Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml) and a solution of NaOH (0.75 g) in methanol (8 ml) was added. The mixture was heated at 50 ° C. for 4.25 hours, cooled to room temperature and stirred overnight. NaOH (0.2 g) was added and the mixture was heated again to 50 ° C. After 5.5 hours, a solution of NaOH (0.2 g) in methanol (8 ml) was added and stirred for 1.5 hours and the mixture was cooled to room temperature and stirred for 1 hour. The product was isolated by filtration under nitrogen, washed with acetone (100 ml) and dried in a vacuum oven at 50 ° C. for 21.5 hours to give 7.26 g of fluvastatin sodium Form CI.

80) Preparation of fluvastatin sodium form CII
Example 179
Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml), filtered and cooled to 10 ° C. A solution of NaOH (0.75 g) in methanol (8 ml) was added and the mixture was stirred at 10 ° C. for 10 hours. During this time, a solution of NaOH (0.4 g) in methanol (4 ml) was added to the mixture in three portions. The product was isolated by filtration under nitrogen, washed with acetone (120 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 5.04 g of fluvastatin sodium Form CII.

81) Preparation of fluvastatin sodium form CIII
Example 180
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) and filtered. A solution of NaOH (0.29 g) in water (1 ml) was added and the mixture was stirred overnight at room temperature. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried in a vacuum oven at 50 ° C. for 22.5 hours to give 1.08 g of fluvastatin sodium Form CIII.

82) Preparation of fluvastatin sodium form CIV
Example 181
Fluvastatin methyl ester (3.0 g) was dissolved in THF (30 ml) and NaOH (1 equivalent) was added. After 2.5 hours, hexane (60 ml) was added and the slurry was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washed with hexane (30 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.2 g (39%) fluvastatin sodium Form CIV.

83) Preparation of fluvastatin sodium CV type
Example 182
Fluvastatin methyl ester (5.0 g) was dissolved in acetonitrile (100 ml) by heating. A solution of NaOH (1 eq) in water (1.25 ml) was added at 50 ° C. and the mixture was stirred at this temperature for 2 hours, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (30 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 1.75 g (34.5%) fluvastatin sodium Form CV.

84) Preparation of fluvastatin sodium crystal Form B
Example 183
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at reflux temperature for 2 hours. After this, no raw material was observed by HPLC. MTBE (58 ml) was added dropwise to the solution over 2 hours. The solution was slowly cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with MTBE (50 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.78 g (91.3%) of fluvastatin sodium Form B.

85) Preparation of amorphous fluvastatin sodium
Example 184
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (40 ml) at 85 ° C. The solution was then cooled to room temperature and stirred at this temperature for 70 hours. The product was filtered under a stream of nitrogen and dried in a vacuum oven at 50 ° C. for 25 hours to give 2.7 g (90%) of amorphous fluvastatin sodium.

Example 185
Fluvastatin methyl ester (3.0 g) was added to cyclohexane (60 ml) and the slurry was heated to reflux. A solution of NaOH (1 eq) in methanol (3 ml) was added to the slurry solution which became clear. After 15 minutes, a precipitate had formed. After an additional hour, the mixture was cooled to room temperature and cyclohexane (40 ml) was added. The mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 2.73 g (90%) of amorphous fluvastatin sodium.

Example 186
A suspension of amorphous fluvastatin (5.0 g) in propan-2-ol (104 ml) was stirred at reflux temperature for 4.5 hours. The suspension was then cooled to room temperature and stirred at this temperature for 16 hours. The product was filtered under nitrogen, washed with propan-2-ol (2 × 10 ml) and dried in a vacuum oven at 50 ° C. for 24 hours to give 3.8 g (76%) of amorphous fluvastatin sodium. Obtained.

Example 187
A 100 ml round bottom flask was charged with fluvastatin-diol-t-butyl ester (20.0 g, 43 mmol), methanol (120 ml), and NaOH (1.82 g) in water (10 ml). The mixture was heated to 35 ° C. The solution became clear and water (50 ml) was added. The mixture was stirred for 3 hours and then the methanol was distilled off. The volume of the mixture was made up to 8 times and the mixture was extracted with MTBE (120 ml). The organic solvent residue was distilled off and the solution was divided into two portions of 68 ml. NaCl (0.7 g) was added to one of the solutions, which was cooled to 4 ° C. over 1 hour. After 1 hour of filtration under nitrogen, the product was isolated and dried in a vacuum oven at 40 ° C. for 24 hours to give 6.04 g (65%) of amorphous fluvastatin sodium crystalline Form D.

Example 188
Fluvastatin-diol-methyl ester (FDME) (4.0 g) was dissolved in acetone (40 ml). A solution of NaOH (0.38 g) in methanol (4 ml) was added and the mixture was stirred at room temperature for 20 hours. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried in a vacuum oven at 50 ° C. for 26 hours to give 3.35 g (82.2%) fluvastatin sodium crystal Form VI.

Example 189
Fluvastatin-diol-methyl ester (FDME) (3.5 g) was dissolved in acetone (35 ml). A solution of NaOH (0.34 g) in methanol (4 ml) was added and the mixture was stirred at room temperature for 22.5 hours. The product was isolated by filtration under nitrogen, washed with acetone (20 ml × 2) and dried in a vacuum oven at 50 ° C. for 26 hours to give 3.22 g (90.3%) of fluvastatin sodium crystal Form VI It was.

1 shows a powder X-ray diffraction pattern of fluvastatin sodium type I. FIG. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type II. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type III. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type IV. 2 shows a DSC thermogram of fluvastatin sodium type IV. Shows the IR spectrum of fluvastatin sodium Form IV scanned by 4000 to 400 ^-1, Figure 6a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 6b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form IV scanned by 4000 to 400 ^-1, Figure 6a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 6b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form IV scanned by 4000 to 400 ^-1, Figure 6a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 6b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type IV-1. 2 shows a DSC thermogram of fluvastatin sodium type IV-1. Shows the IR spectrum of fluvastatin sodium IV-1 type scanned by 4000 to 400 ^-1, Figure 9a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 9b a 1500～400Cm ^-1 region of the spectrum It is expanding. Shows an IR spectrum of fluvastatin sodium IV-1 type scanned by 4000 to 400 ^-1, Figure 9a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 9b a 1500～400Cm ^-1 region of the spectrum It is expanding. Shows the IR spectrum of fluvastatin sodium IV-1 type scanned by 4000 to 400 ^-1, Figure 9a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 9b a 1500～400Cm ^-1 region of the spectrum It is expanding. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium Form V. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type VI. 2 shows a DSC thermogram of fluvastatin sodium type VI. Shows the IR spectrum of fluvastatin sodium Form VI scanned by 4000 to 400 ^-1, Figure 13a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 13b enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form VI scanned by 4000 to 400 ^-1, Figure 13a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 13b enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form VI scanned by 4000 to 400 ^-1, Figure 13a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 13b enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type VII. 2 shows a DSC thermogram of fluvastatin sodium type VII. Shows the IR spectrum of fluvastatin sodium Form VII scanned by 4000 to 400 ^-1, Figure 16a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 16b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form VII scanned by 4000 to 400 ^-1, Figure 16a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 16b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form VII scanned by 4000 to 400 ^-1, Figure 16a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 16b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type IX. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type IX-1. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XI. 2 shows a DSC thermogram of fluvastatin sodium type XI. Shows the IR spectrum of fluvastatin sodium Form XI scanned by 4000 to 400 ^-1, Figure 21a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 21b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form XI scanned by 4000 to 400 ^-1, Figure 21a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 21b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form XI scanned by 4000 to 400 ^-1, Figure 21a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 21b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XI-2 form. 2 shows a DSC thermogram of fluvastatin sodium XI-2 type. Shows the IR spectrum of fluvastatin sodium XI-2 type scanned by 4000 to 400 ^-1, Figure 24a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 24b is a 1500～400Cm ^-1 region of the spectrum It is expanding. Shows the IR spectrum of fluvastatin sodium XI-2 type scanned by 4000 to 400 ^-1, Figure 24a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 24b is a 1500～400Cm ^-1 region of the spectrum It is expanding. Shows the IR spectrum of fluvastatin sodium XI-2 type scanned by 4000 to 400 ^-1, Figure 24a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 24b is a 1500～400Cm ^-1 region of the spectrum It is expanding. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XIII. The powder X-ray diffraction pattern of fluvastatin sodium XV type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XVI. 2 shows a DSC thermogram of fluvastatin sodium type XVI. Shows the IR spectrum of fluvastatin sodium Form XVI scanned by 4000 to 400 ^-1, Figure 33a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 33b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form XVI scanned by 4000 to 400 ^-1, Figure 33a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 33b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium Form XVI scanned by 4000 to 400 ^-1, Figure 33a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 33b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Fig. 2 shows a powder X-ray diffraction pattern of fluvastatin sodium type XVII. 2 shows a DSC thermogram of fluvastatin sodium type XVII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XVIII form. 2 shows a DSC thermogram of fluvastatin sodium type XVIII. Shows the IR spectrum of fluvastatin sodium type XVIII scanned by 4000 to 400 ^-1, Figure 38a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 38b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium type XVIII scanned by 4000 to 400 ^-1, Figure 38a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 38b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium type XVIII scanned by 4000 to 400 ^-1, Figure 38a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 38b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XIX. 2 shows a DSC thermogram of fluvastatin sodium type XIX. Shows the IR spectrum of fluvastatin sodium XIX type scanned by 4000 to 400 ^-1, Figure 41a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 41b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium XIX type scanned by 4000 to 400 ^-1, Figure 41a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 41b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium XIX type scanned by 4000 to 400 ^-1, Figure 41a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 41b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XIX-1. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium form XX. 2 shows a DSC thermogram of fluvastatin sodium type XX. Shows the IR spectrum of fluvastatin sodium XX type scanned by 4000 to 400 ^-1, Figure 45a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 45b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium XX type scanned by 4000 to 400 ^-1, Figure 45a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 45b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. Shows the IR spectrum of fluvastatin sodium XX type scanned by 4000 to 400 ^-1, Figure 45a is an enlarged 4000～1500Cm ^-1 region of the spectrum, Figure 45b is an enlarged 1500～400Cm ^-1 region of the spectrum ing. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XXII. Fig. 2 shows a powder X-ray diffraction pattern of fluvastatin sodium form XXIII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXIV. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XXVI. Fig. 2 shows a powder X-ray diffraction pattern of fluvastatin sodium type XXVII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXIX. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXX type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXI type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXIII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXIV type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXV type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXVI type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXVII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXVIII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XXXIX. The powder X-ray diffraction pattern of fluvastatin sodium XLI type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLII form. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLIII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLIV type. The powder X-ray diffraction pattern of fluvastatin sodium XLV type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLVI type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLVII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLVIII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XLIX type. The powder X-ray diffraction pattern of fluvastatin sodium L-form is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LI type. The powder X-ray diffraction pattern of fluvastatin sodium LIII type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LIV type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LV type. The powder X-ray diffraction pattern of fluvastatin sodium LVI type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LVII type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LVIII form. The powder X-ray diffraction pattern of fluvastatin sodium LX type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXIV type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXV type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXVI type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXVII type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LXVIII type. The powder X-ray diffraction pattern of fluvastatin sodium LXIX type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXX type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXI type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXII type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXIV type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXV type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXVI type is shown. The powder X-ray diffraction pattern of fluvastatin sodium LXXVII type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium LXXVIII type. The powder X-ray diffraction pattern of fluvastatin sodium XC type is shown. The powder X-ray diffraction pattern of fluvastatin sodium XCI type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCIII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCIV type. The powder X-ray diffraction pattern of fluvastatin sodium XCV type is shown. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCVI type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCVII type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type XCVIII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium XCIX type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type C. FIG. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium CI type. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type CII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium type CIII. 1 shows a powder X-ray diffraction pattern of fluvastatin sodium CIV type. The powder X-ray diffraction pattern of fluvastatin sodium CV type is shown.

Claims (445)

  Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 11.3, 13.1, 17.9, 18.4, and 21.8 ± 0.2 degrees (2θ).   The crystal form of claim 1, wherein the crystal form is substantially characterized by the PXRD pattern described in FIG.   2. The crystal form of claim 1, wherein the crystal form is fluvastatin sodium form I. Method for the preparation of crystalline fluvastatin sodium form I comprising:
a) contacting a lower alkyl ester of fluvastatin with sodium in a solvent selected from the group consisting of acetone and acetonitrile,
b) precipitating fluvastatin sodium form I from the solvent, and
c) Separate the solvent from Form I. Method for the preparation of crystalline fluvastatin sodium form I comprising:
a) dissolving fluvastatin sodium in a solvent selected from a mixture of acetone, butan-2-ol and water;
b) crystallized form I from the solvent, and
c) Separate the solvent from Form I.   Crystalline form of fluvastatin sodium, characterized by a PXRD pattern with a peak at 3.6 ± 0.2 degrees (2θ).   7. The crystal form of claim 6 characterized by a PXRD pattern having peaks at 5.4, 5.7, 10.7, and 20.3 ± 0.2 degrees (2θ).   The crystal form of claim 7, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   7. The crystal form of claim 6, wherein the crystal form is fluvastatin sodium form B. Process for the preparation of crystalline fluvastatin sodium Form II comprising:
a) dissolving fluvastatin sodium in a solvent selected from a mixture of butan-1-ol and propan-2-ol;
b) crystallize Form II from the solvent, and
c) Separate the solvent from Form II.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 9.5, 10.1, 10.9, and 20.1 ± 0.2 degrees (2θ).   12. The crystal form of claim 11, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   12. The crystal form of claim 11, wherein the crystal form is fluvastatin sodium form III. A process for the preparation of crystalline fluvastatin sodium form III comprising:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of butan-1-ol, ethyl acetate, and THF;
b) slowly adding an antisolvent selected from the group consisting of MTBE, hexane, and cyclohexane to the solvent to induce type III precipitation; and
c) Separate the solvent and anti-solvent from Form III. A process for the preparation of crystalline fluvastatin sodium form III comprising:
a) Dissolve amorphous fluvastatin sodium in refluxing ethanol,
b) precipitating form III from ethanol, and
c) Separate ethanol from Form III. A process for the preparation of crystalline fluvastatin sodium form III comprising:
a) Suspend fluvastatin sodium form XIV in refluxing ethanol for a time sufficient to effect conversion to form III,
b) cool the ethanol to ambient temperature, and
c) Separate ethanol from Form III.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 4.0, 9.8, 10.8, and 22.0 ± 0.2 degrees (2θ).   The crystal form of claim 17, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   The crystal form of claim 17, wherein the crystal form is fluvastatin sodium form IV.   The fluvastatin sodium of claim 17 having a water content of about 4% by weight. Process for the preparation of crystalline fluvastatin sodium Form IV comprising the following steps:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of THF, propan-2-ol, 1,4-dioxane, and butan-1-ol to form a solution;
b) heating the solvent to reflux the solution, where heating is initiated before or after dissolving the fluvastatin sodium,
c) adding an organic antisolvent to the reflux solution to induce precipitation of fluvastatin sodium type IV, and
d) Separate fluvastatin sodium type IV from solvent and antisolvent.   21. The method of claim 20, wherein the anti-solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, n-pentane, cyclohexane, and methyl t-butyl ether.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 4.0, 9.6, 18.5, and 22.2 ± 0.2 degrees (2θ).   24. The crystal form of claim 23, further characterized by peaks at 6.6, 10.4, 11.0, 17.3, 19.5, 20.1, 20.7, and 21.3 ± 0.2 degrees (2θ).   25. The crystal form of claim 24, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   24. The crystal form of claim 23, wherein the crystal form is fluvastatin sodium form IV-1. Method for preparing fluvastatin sodium Form IV-1, comprising the following steps:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of THF, butan-2-ol, and 1,4-dioxane to form a solution;
b) heating the solvent to reflux the solution, where heating is initiated before or after dissolving the fluvastatin sodium,
c) adding an organic anti-solvent to the refluxing solution to induce precipitation of fluvastatin sodium type IV-1; and
d) Separate fluvastatin sodium type IV from solvent and antisolvent.   28. The method of claim 27, wherein the antisolvent is selected from the group consisting of n-pentane, cyclohexane, and MTBE.   Fluvastatin sodium type IV-1 having a moisture content of about 2 to about 3% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.8, 6.3, 9.5, and 21.1 ± 0.2 degrees (2θ).   32. The crystal form of claim 30, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   30. The crystal form of claim 29, wherein the crystal form is fluvastatin sodium form V. A method for preparing crystalline fluvastatin sodium Form V comprising:
a) Dissolve fluvastatin sodium in refluxing butan-1-ol,
b) Slowly add heptane to the reflux solution,
c) precipitating form V from the solution, and
d) Separate butan-1-ol and heptane from Form V. A method for preparing crystalline fluvastatin sodium Form V comprising:
a) Fluvastatin sodium is dissolved in a three solvent system of ethanol: ethyl acetate: propan-1-ol at reflux temperature.
b) add hexane to the solution,
c) precipitating form V from the solution, and
d) Separate ethanol, ethyl acetate, propan-1-ol, and n-hexane from Form V.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 4.7, 5.7, 10.9, 12.2, and 19.9 ± 0.2 degrees (2θ).   36. The crystal form of claim 35, further characterized by peaks at 9.1, 9.6, 14.3, 16.3, 16.9, 20.4, and 21.3 ± 0.2 degrees (2θ).   38. The crystal form of claim 36, further characterized by substantially the PXRD pattern of FIG.   36. The crystal form of claim 35, wherein the crystal form is fluvastatin sodium form VI. A method for preparing fluvastatin sodium Form VI comprising the following steps:
a) Dissolve fluvastatin sodium in DMF at room temperature to form a solution,
b) adding an organic anti-solvent to this solution to induce precipitation of fluvastatin sodium type VI, and
d) Separate fluvastatin sodium type VI from DMF and poor solvent. Process for the preparation of fluvastatin sodium Form VI comprising:
a) about 1 molar equivalent of sodium hydroxide solution in a solvent system selected from the group consisting of lower alkyl esters of fluvastatin, methanol, ethanol, a mixture of methanol and water, and a mixture of butan-1-ol and water Dissolve in
b) adding an anti-solvent selected from the group consisting of acetonitrile and acetone to the solution at an elevated temperature; and
c) Separate form VI from the solvent system.   41. The method of claim 40, wherein the antisolvent is selected from the group consisting of diethyl ether and hexane.   Fluvastatin sodium Form VI having a moisture content of about 5 to about 6% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 4.3, 5.8, 8.6, and 20.7 ± 0.2 degrees (2θ).   44. The crystal form of claim 43, further characterized by peaks at 10.8, 12.3, 13.7, 15.8, 17.3, 19.4, 22.0, 23.9, 25.2, 26.2, and 27.6 ± 0.2 degrees (2θ).   45. The crystal form of claim 44, further characterized by substantially the PXRD pattern of FIG.   44. The crystal form of claim 43, wherein the crystal form is fluvastatin sodium form VII. A process for preparing fluvastatin sodium Form VII comprising the following steps:
a) Dissolve fluvastatin sodium in DMF at room temperature to form a solution,
b) adding an organic anti-solvent to induce precipitation of fluvastatin sodium type VII from this solution; and
d) Separate fluvastatin sodium type VII from DMF and antisolvent.   48. The method of claim 47, wherein the antisolvent is selected from the group consisting of chloroform, MTBE, dichloromethane, cyclohexane, and 1,2-dichloroethane. A process for preparing fluvastatin sodium Form VII comprising the following steps:
a) Fluvastatin in a solution of about 1 molar equivalent of sodium hydroxide in a solvent system selected from the group consisting of methanol, butan-1-ol, and a mixture of butan-1-ol and propan-2-ol. Dissolves lower alkyl esters,
b) adding an antisolvent selected from the group consisting of acetone, acetonitrile, and methyl tert-butyl ether to induce precipitation of type VII; and
c) Separate solvent system and anti-solvent from Form VII. A process for preparing fluvastatin sodium Form VII comprising the following steps:
a) A lower alkyl ester of fluvastatin is dissolved in acetonitrile.
b) adding a solution of about 1 molar equivalent of sodium hydroxide in ethanol to induce precipitation of type VII, and
c) Separate acetonitrile and ethanol from Form VII.   Fluvastatin sodium Form VII having a moisture content of about 1 to about 9% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 10.0, and 19.7 ± 0.2 degrees (2θ).   53. The crystal form of claim 52, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   53. The crystal form of claim 52, wherein the crystal form is fluvastatin sodium form IX. A process for the preparation of crystalline fluvastatin sodium form IX comprising:
a) Dissolve fluvastatin sodium in 1,4-dioxane,
b) Dichloromethane is added to this solution to induce type IX precipitation, and
c) Separate 1,4-dioxane and dichloromethane from Form IX. A process for the preparation of crystalline fluvastatin sodium form IX comprising:
a) Dissolve fluvastatin sodium in ethanol,
b) Add ethyl acetate to this solution to induce precipitation of type IX, and
c) Separate ethanol and ethyl acetate from Form IX. A process for the preparation of crystalline fluvastatin sodium form IX comprising:
a) dissolving fluvastatin sodium in a solvent system selected from the group consisting of diethyl ether, n-pentane, and a mixture of ethanol and methanol;
b) Add hexane to induce type IX precipitation, and
c) Separate the solvent system from Form IX. A process for the preparation of crystalline fluvastatin sodium form IX comprising:
a) Suspend fluvastatin sodium Form B in refluxing ethyl acetate for a time sufficient to effect conversion to Form IX; and
b) Separate ethyl acetate from Form IX. A process for the preparation of crystalline fluvastatin sodium form IX comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with about 1 molar equivalent of sodium in ethanol at elevated temperature;
b) adding an excess of propan-2-ol to ethanol relative to ethanol;
c) precipitating type IX, and
d) Separate ethanol and propan-2-ol from Form IX.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 6.6, 10.0, 13.2, and 19.8 ± 0.2 degrees (2θ).   61. The crystal form of claim 60, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   61. The crystal form of claim 60, wherein the crystal form is fluvastatin sodium form IX-1. Process for the preparation of crystalline fluvastatin sodium Form IX-1 comprising:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of butan-1-ol, ethyl acetate, isobutyl acetate, ethanol, toluene, tetrahydrofuran, and methyl ethyl ketone;
b) adding to this solvent an anti-solvent selected from the group consisting of n-pentane, diethyl ether, methyl tert-butyl ether, dichloromethane, hexane, and cyclohexane, to induce precipitation of type IX-1; and
c) Separate solvent and anti-solvent from Form IX-1.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.3, 3.8, 4.6, 8.3, 10.2, and 25.1 ± 0.2 degrees (2θ).   65. The crystal form of claim 64, characterized by a PXRD pattern having peaks at 7.2, 11.4, 12.4, 13.6, 16.0, 16.9, 17.4, 20.4, 21.3, 21.9, and 23.1 ± 0.2 degrees (2θ).   68. The crystal form of claim 65, further characterized by substantially the PXRD pattern of FIG.   65. The crystal form of claim 64, wherein the crystal form is fluvastatin sodium form XI. A method for preparing fluvastatin sodium form XI comprising the following steps:
a) Dissolve fluvastatin sodium in butan-2-ol to form a solution,
b) Heating butan-2-ol to reflux the solution, where heating is initiated before or after dissolving the fluvastatin sodium,
c) precipitating fluvastatin sodium form XI from the solution, and
d) Separate fluvastatin sodium form XI from butan-2-ol.   69. The method of claim 68, wherein the precipitation is induced by adding an organic antisolvent to the solution.   69. The method of claim 68, wherein the organic antisolvent is selected from the group consisting of hexane, n-pentane, methyl tert-butyl ether, diethyl ether, and chloroform.   Fluvastatin sodium Form XI having a moisture content of about 1 to about 6% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 3.8, 4.6, 10.4, and 18.5 ± 0.2 degrees (2θ).   73. The crystal form of claim 72, further characterized by peaks at 8.5, 11.2, 12.1, 16.4, 17.0, 17.7, 20.9, 21.2, 21.7, 22.2, and 23.6 ± 0.2 degrees (2θ).   74. The crystal form of claim 73, further characterized by substantially the PXRD pattern of FIG.   73. The crystal form of claim 72, wherein the crystal form is fluvastatin sodium form XI-2. Process for the preparation of fluvastatin sodium form XI-2 comprising the following steps:
a) Dissolve fluvastatin sodium in propan-1-ol to form a solution,
b) Heating propan-1-ol to reflux the solution, where heating is initiated before or after dissolving the fluvastatin sodium,
c) adding an organic anti-solvent to the refluxing solution to induce precipitation of fluvastatin sodium type XI-2, and
d) Separate fluvastatin sodium form XI-2 from propan-1-ol and antisolvent.   77. The method of claim 76, wherein the antisolvent is selected from the group consisting of hexane, MTBE, and dichloromethane.   Fluvastatin sodium Form XI-2 having a moisture content of about 2 to about 3% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.1, 6.5, 9.8, 17.6, 25.9, and 30.9 ± 0.2 degrees (2θ).   80. The crystal form of claim 79, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   80. The crystal form of claim 79, wherein the crystal form is fluvastatin sodium form XII. Process for the preparation of fluvastatin sodium form XII comprising:
a) Dissolve fluvastatin sodium in butan-1-ol,
b) Inducing precipitation of Form XII by adding 1,4-dioxane to butan-1-ol, and
c) Separate 1,4-dioxane and butan-1-ol from Form XII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.8, 5.6, 12.3, and 20.6 ± 0.2 degrees (2θ).   84. The crystal form of claim 83, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   84. The crystal form of claim 83, wherein the crystal form is fluvastatin sodium form XIII. Process for the preparation of fluvastatin sodium form XIII comprising:
a) Suspend fluvastatin sodium form B in acetonitrile at high temperature,
b) cooling the suspension to induce precipitation of type XIII, and
c) Acetonitrile is separated from Form XIII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.8 and 7.0 ± 0.2 degrees (2θ).   90. The crystal form of claim 87, further characterized by peaks at 4.3, 10.2, 10.7, 11.2, 15.6, 17.8, 18.4, and 19.5 ± 0.2 degrees (2θ).   90. The crystal form of claim 88, further characterized by substantially the PXRD pattern of FIG.   90. The crystal form of claim 87, wherein the crystal form is fluvastatin sodium form XVI. A process for preparing fluvastatin sodium form XVI of any claim comprising the following steps:
a) Dissolve fluvastatin sodium in propan-2-ol to form a solution,
b) Propan-2-ol is heated to reflux the solution, where heating is initiated before or after dissolving the fluvastatin sodium,
c) dichloromethane is added to the refluxing solution to precipitate fluvastatin form XVI, and
d) Separate fluvastatin sodium form XVI from propan-2-ol.   Fluvastatin sodium Form XVI having a moisture content of about 3 to about 4% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5 (broad), 5.4, 5.8, and 13.8 ± 0.2 degrees (2θ).   94. The crystal form of claim 93, further characterized by peaks at 10.8, 14.8, 16.4, 19.4, 21.5, and 22.7 ± 0.2 degrees (2θ).   95. The crystal form of claim 94, further characterized by a PXRD pattern substantially as shown in FIG.   94. The crystal form of claim 93, wherein the crystal form is fluvastatin sodium form XVII. A process for preparing fluvastatin sodium form XVII of any claim comprising the following steps:
a) Dissolve fluvastatin sodium in propan-1-ol at high temperature,
b) crystallizing fluvastatin sodium from propan-1-ol at high temperature, and
c) Separate fluvastatin sodium form XVII from propan-1-ol.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 8.4, 10.0, and 10.9 ± 0.2 degrees (2θ).   99. The crystal form of claim 98, further characterized by peaks at 11.7, 12.6, 15.8, 17.4, 18.0, 18.8, 20.0, 20.7, and 21.3 ± 0.2 degrees (2θ).   100. The crystal form of claim 99, further characterized by a PXRD pattern substantially as in FIG.   99. The crystal form of claim 98, wherein the crystal form is fluvastatin sodium form XVIII. Process for the preparation of fluvastatin sodium form XVIII comprising the following steps:
a) producing a slurry of fluvastatin sodium in methyl ethyl ketone;
b) refluxing the slurry for a time sufficient to substantially convert fluvastatin sodium to fluvastatin sodium Form XVIII, and
c) Separate fluvastatin sodium form XVIII from the slurry.   Fluvastatin sodium form XVIII having a water content of about 4% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 10.1, 13.5, and 18.0 ± 0.2 degrees (2θ).   105. The crystal form of claim 104, further characterized by peaks at 6.8, 20.1, 21.8, and 25.6 ± 0.2 degrees (2θ).   106. The crystal form of claim 105, further characterized by substantially the PXRD pattern of FIG.   105. The crystal form of claim 104, wherein the crystal form is fluvastatin sodium form XIX. Process for the preparation of fluvastatin sodium form XIX comprising the following steps:
a) Conversion of a crystalline form of fluvastatin sodium selected from the group consisting of type XI, type IV-1 and type XVI to fluvastatin sodium type XIX under conditions of 60% or higher relative humidity Maintain enough time to do, and
b) Remove fluvastatin sodium form XIX from 60% or higher relative humidity conditions.   Fluvastatin sodium Form XIX having a moisture content of about 19 to about 28% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 10.4, 11.9, 14.0, and 22.5 ± 0.2 degrees (2θ).   111. The crystal form of claim 110, further characterized by peaks at 17.5, 17.8, 18.0, 18.3, 25.4 ± 0.2 degrees (2θ).   112. The crystal form of claim 111, further characterized by substantially the PXRD pattern of FIG.   111. The crystal form of claim 110, wherein the crystal form is fluvastatin sodium form XIX-1. A process for the preparation of crystalline fluvastatin sodium form XIX-1 comprising:
a) producing a heterogeneous mixture of fluvastatin sodium XI and water,
b) maintain a heterogeneous mixture to obtain Form XIX-1, and
c) Fluvastatin sodium Form XIX-1 is recovered from the mixture.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 10.1, 13.5, 18.0, and 20.8 ± 0.2 degrees (2θ).   119. The crystal form of claim 115, further characterized by peaks at 5.9 and 12.4 ± 0.2 degrees (2θ).   119. The crystal form of claim 116, further characterized by substantially the PXRD pattern of FIG.   116. The crystal form of claim 115, wherein the crystal form is fluvastatin sodium form XX. A method for preparing fluvastatin sodium form XX comprising the following steps:
a) maintaining fluvastatin sodium form VII for a time sufficient to effect conversion to fluvastatin sodium form XX under conditions of 80% relative humidity; and
b) Remove fluvastatin sodium form XX from 80% relative humidity.   Fluvastatin sodium form XX, having a water content of about 19% by weight.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.2, 12.4, and 18.3 ± 0.2 degrees (2θ).   122. The crystal form of claim 121, further characterized by peaks at 6.4, 9.5, 15.6, and 21.4 ± 0.2 degrees (2θ).   The crystal form of claim 122, further characterized by substantially the PXRD pattern of FIG.   122. The crystal form of claim 121, wherein the crystal form is fluvastatin sodium form XXII. Process for the preparation of crystalline fluvastatin sodium form XXII comprising:
a) contacting fluvastatin sodium form XV with water vapor in a container containing air of controlled high humidity relative to the air outside the container for a time effective to convert form XV to form XXII; and
b) Stop the humidity control in the container or remove the Model XV from the container.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 4.0, 4.4, 17.1, and 19.3 ± 0.2 degrees (2θ).   129. The crystal form of claim 126, further characterized by peaks at 6.2, 7.2, 9.3, 10.2, and 18.6 ± 0.2 degrees (2θ).   128. The crystal form of claim 127, further characterized by substantially the PXRD pattern of FIG.   127. The crystal form of claim 126, wherein the crystal form is fluvastatin sodium form XXIII. Process for the preparation of crystalline fluvastatin sodium form XXIII comprising:
a) Dissolve fluvastatin sodium in propan-1-ol at high temperature,
b) Form XXIII is precipitated from propan-1-ol,
c) Propanan-1-ol is separated from Form XXIII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 10.2, 13.6, 17.9, and 18.7 ± 0.2 degrees (2θ).   132. The crystal form of claim 131, further characterized by peaks at 6.9, 10.7, 12.0, 22.5, and 25.4 ± 0.2 degrees (2θ).   135. The crystal form of claim 132, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   132. The crystal form of claim 131, wherein the crystal form is fluvastatin sodium form XXIV. Process for the preparation of crystalline fluvastatin sodium form XXIV comprising:
a) Dissolve fluvastatin sodium in water,
b) precipitating form XXIV from water, and
c) Separate water from Form XXIV.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.8, 15.0, 18.5, 21.6, and 25.8 ± 0.2 degrees (2θ).   138. The crystal form of claim 136, further characterized by peaks at 11.7, 15.9, 16.2, 24.3, and 35.2 ± 0.2 degrees (2θ).   138. The crystal form of claim 137, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   138. The crystal form of claim 136, wherein the crystal form is fluvastatin sodium form XXIV. Method for preparing crystalline fluvastatin sodium form XXVI comprising:
a) Dissolve fluvastatin sodium in 1,4-dioxane: water mixture at high temperature,
b) cooling the mixture to induce precipitation of type XXVI, and
c) Separate the mixture from Form XXVI.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.3, 3.9, 15.9, 18.4, and 21.6 ± 0.2 degrees (2θ).   142. The crystal form of claim 141, further characterized by peaks at 8.4, 15.0, 17.9, 24.3, and 25.7 ± 0.2 degrees (2θ).   143. The crystal form of claim 142, wherein the crystal form is substantially characterized by the PXRD pattern of FIG.   142. The crystal form of claim 141, wherein the crystal form is fluvastatin sodium form XXVII. Process for the preparation of crystalline fluvastatin sodium form XXVII comprising:
a) Dissolve fluvastatin sodium in 1,4-dioxane: water mixture at high temperature,
b) add hexane to the mixture at high temperature,
c) cooling the mixture,
d) precipitating form XXVII, and
e) Separate 1,4-dioxane, water, and hexane from Form XXVII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.4, 5.9, 6.8, 7.9, 10.8 ± 0.2 degrees (2θ).   147. The crystal form of claim 146, further characterized by peaks at 14.3, 15.6, 17.5, 19.7, 21.3, 22.7 ± 0.2 degrees (2θ).   148. The crystal form of claim 147, further characterized by substantially the PXRD pattern of FIG.   147. The crystal form of claim 146, wherein the crystal form is fluvastatin sodium form XXIX. Process for the preparation of fluvastatin sodium form XXIX comprising the following steps:
a) producing a heterogeneous mixture of fluvastatin sodium form XV and 1,4-dioxane;
b) maintaining a heterogeneous mixture for a time sufficient to substantially convert Form XV to Form XXIX; and
c) Separate form XXIX from 1,4-dioxane.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.4, 5.8, 10.8, 13.8, 14.8 ± 0.2 degrees (2θ).   152. The crystal form of claim 151, further characterized by peaks at 16.4, 19.0, 19.5, 20.2, 20.8, 21.5, 22.7 ± 0.2 ± 0.2 degrees (2θ).   153. The crystal form of claim 152, further characterized by substantially the PXRD pattern of FIG.   152. The crystal form of claim 151, wherein the crystal form is fluvastatin sodium form XXX. Method for preparing fluvastatin sodium form XXX comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form XV and a diluent selected from the group consisting of methyl ethyl ketone, tetrahydrofuran, acetone, butan-2-ol, and butan-1-ol;
b) maintaining a heterogeneous mixture to substantially convert type XV to type XXX, and
c) Separate form XXX from diluent. Method for preparing fluvastatin sodium form XXX comprising:
a) dissolving the lower alkyl ester of fluvastatin in a solution containing a molar excess of sodium hydroxide relative to fluvastatin in a mixture of methanol and water;
b) adding acetone to the solution at high temperature to induce type XXX precipitation, and
c) Separate methanol and water from Form XXX.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.3, 6.1, 6.5, 11.9, 13.2 ± 0.2 degrees (2θ).   158. The crystal form of claim 157, further characterized by peaks at 8.0, 8.5, 9.3, 16.3, 18.3, 20.2, 20.6, 21.1 ± 0.2 degrees (2θ).   158. The crystal form of claim 158, further characterized by substantially the PXRD pattern of FIG.   158. The crystal form of claim 157, wherein the crystal form is fluvastatin sodium form XXXI. Method for preparing fluvastatin sodium Form XXXI comprising:
a) producing a heterogeneous mixture of fluvastatin sodium form XV and ethanol,
b) maintain the heterogeneous mixture for a time sufficient to perform conversion of Form XV to Form XXXI; and
c) Separate ethanol from Form XXXI.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.0, 5.5, 8.0, 9.1, 13.4, 16.6, 21.2 ± 0.2 degrees (2θ).   163. The crystal form of claim 162, further characterized by peaks at 6.6, 8.8, 10.4, 11.6, 12.0, 14.1, 14.8, 16.1, 17.9, 18.5, 19.7, 20.3, 24.3, 24.9, 26.7 ± 0.2 degrees (2θ).   164. The crystal form of claim 163, further characterized by substantially the PXRD pattern of FIG.   163. The crystal form of claim 162, wherein the crystal form is fluvastatin sodium XXXIII form.   163. The crystal form of claim 162, having a moisture content of about 7% by weight. Process for the preparation of crystalline fluvastatin sodium form XXXIII comprising:
a) producing a heterogeneous mixture of fluvastatin sodium XV or B and ethanol,
b) maintain the heterogeneous mixture for a time sufficient to substantially convert Form XV or Form B to Form XXXIII, and
c) Fluvastatin sodium Form XXXIII is recovered from the mixture.   168. The method of claim 167, wherein the heterogeneous mixture is maintained at an elevated temperature and then cooled or allowed to cool before recovering Form XXXIII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.4, 6.1, 7.6, 18.5, 21.1 ± 0.2 degrees (2θ).   170. The crystal form of claim 169, further characterized by peaks at 8.8, 9.3, 12.4, 13.1, 14.3, 15.2, 15.9, 17.2, 17.6, 20.5, 22.2, 24.1, 25.4, 26.2 ± 0.2 degrees (2θ).   170. The crystal form of claim 170, further characterized by a PXRD pattern substantially as in FIG.   170. The crystal form of claim 169, wherein the crystal form is fluvastatin sodium XXXIV. A process for the preparation of crystalline fluvastatin sodium form XXXIV comprising:
a) sufficient time to produce a heterogeneous mixture of fluvastatin sodium Form XV and DMSO,
b) maintain the mixture for a time sufficient to substantially convert Form XV to Form XXXIV; and
c) Fluvastatin sodium Form XXXIV is recovered from the mixture.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.4, 6.0, 9.9, 14.8, 21.0 ± 0.2 degrees (2θ).   175. The crystal form of claim 174, further characterized by peaks at 16.7, 18.6, 19.8, 22.6 ± 0.2 degrees (2θ).   175. The crystal form of claim 175, further characterized by a PXRD pattern substantially as shown in FIG.   175. The crystal form of claim 174, wherein the crystal form is fluvastatin sodium XXXV. Method for the preparation of crystalline fluvastatin sodium form XXXV comprising:
a) producing a heterogeneous mixture of fluvastatin sodium form XV and DMF,
b) maintaining a heterogeneous mixture for a time sufficient to substantially convert Form XV to Form XXXV; and
c) Recover form XXXV from the heterogeneous mixture.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.0, 9.2, 11.5, 14.4, and 20.2 ± 0.2 degrees (2θ).   180. The crystal form of claim 179, further characterized by peaks at 9.6, 12.3, and 12.8 ± 0.2 degrees (2θ).   181. The crystal form of claim 180, further characterized by substantially the PXRD pattern of FIG.   180. The crystal form of claim 179, wherein the crystal form is fluvastatin sodium form XXXVI. Process for the preparation of crystalline fluvastatin sodium form XXXVI comprising:
a) Suspend fluvastatin sodium XI-wet form V in water for a time sufficient to effect the conversion of XI-wet form to XXXVI, and
b) Separate water from Form XXXVI.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.63, 10.36, 13.74, 17.93, 18.34 ± 0.2 degrees (2θ).   185. The crystal form of claim 184, further characterized by peaks at 11.26, 12.16, 12.91, 19.44, 20.57 ± 0.2 degrees (2θ).   186. The crystal form of claim 185, further characterized by substantially the PXRD pattern of FIG.   185. The crystal form of claim 184, wherein the crystal form is fluvastatin sodium form XXXVII. Process for the preparation of crystalline fluvastatin sodium form XXXVII comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form XI and water at ambient temperature;
b) convert the form XI to form XXXVII, maintaining the heterogeneous mixture at ambient temperature, and
c) Fluvastatin sodium Form XXXVII is recovered from the mixture.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.64, 4.66, 7.30, 8.84, 11.61 ± 0.2 degrees (2θ).   189. The crystal form of claim 189, further characterized by peaks at 19.08, 19.65, 21.15, 22.59, 24.20 ± 0.2 degrees (2θ).   202. The crystal form of claim 190, further characterized by substantially the PXRD pattern of FIG.   189. The crystal form of claim 189, wherein the crystal form is fluvastatin sodium form XXXVIII. Process for the preparation of crystalline fluvastatin sodium form XXXVIII comprising:
a) producing a heterogeneous mixture of fluvastatin type XI and absolute ethanol,
b) maintaining the mixture to convert form XI to form XXXVIII, and
c) Recover Form XXXVIII from the mixture. Process for the preparation of crystalline fluvastatin sodium form XXXVIII comprising:
a) Dissolve the lower alkyl ester of fluvastatin in about 1 molar equivalent sodium hydroxide solution in ethanol;
b) Induction of type XXXVIII precipitation by addition of ethyl acetate, and
b) Separate form XXXVIII from ethanol and ethyl acetate.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 4.5, 8.5, 17.8, 20.1 ± 0.2 degrees (2θ).   202. The crystal form of claim 195, further characterized by peaks at 6.9, 11.2, 16.8, 19.6, and 21.6 ± 0.2 degrees (2θ).   196. The crystal form of claim 196, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   202. The crystal form of claim 195, wherein the crystal form is fluvastatin sodium form XXXIX. A process for the preparation of crystalline fluvastatin sodium form XXXIX comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with about 1 molar equivalent of sodium hydroxide in ethanol;
b) adding an excess of propan-2-ol to ethanol relative to ethanol;
c) precipitating XXXIX, and
d) Separate ethanol and propan-2-ol from Form XXXIX.   Crystal form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.75, 4.31, 9.10, 11.00 ± 0.2 degrees (2θ).   200. The crystal form of claim 200, further characterized by peaks at 5.60, 7.30, 7.55, 14.50, 18.04 ± 0.2 degrees (2θ).   202. The crystal form of claim 201, further characterized by substantially the PXRD pattern of FIG.   200. The crystal form of claim 200, wherein the crystal form is fluvastatin sodium XLI form. Method for the preparation of crystalline fluvastatin sodium form XLI comprising:
a) Dissolve fluvastatin sodium in water,
b) adding acetonitrile to water to induce XLI-type precipitation, and
c) Separate acetonitrile and water from Form XLI.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 9.7, 11.0, 18.9 ± 0.2 degrees (2θ).   207. The crystal form of claim 205, further characterized by peaks at 5.7, 14.8, 16.1, 17.0, 22.6 ± 0.2 degrees (2θ).   207. The crystal form of claim 206, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   206. The crystal form of claim 205, wherein the crystal form is fluvastatin sodium XLII form. Process for the preparation of fluvastatin sodium Form XLII comprising:
a) Dissolve fluvastatin sodium in methyl ethyl ketone,
b) Add sodium hydroxide solution in methanol to this solution to induce precipitation of XLII type, and
c) Separate the solution from Form XLII. Process for the preparation of fluvastatin sodium Form XLII comprising:
a) Dissolve fluvastatin in methanol,
b) Add solid sodium hydroxide solution to this solution at high temperature,
c) cool the solution,
d) Add ethyl acetate to form a XLII type slurry in methanol, and
e) Separate XLII from methanol. Process for the preparation of fluvastatin sodium Form XLII comprising:
a) Dissolve fluvastatin diol in a solution of dichloromethane,
b) NaOH dissolved in methanol is added to this solution to induce XLII type precipitation, and
c) Separate the solution from Form XLII. Process for the preparation of fluvastatin sodium Form XLII comprising:
a) Dissolve fluvastatin in dichloromethane,
b) Add ethanolic or methanolic sodium hydroxide to this solution,
c) precipitating XLII from this solution, and
d) Separate XLII from the solution.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.25, 5.29, 6.59, 8.60 ± 0.2 degrees (2θ).   224. The crystal form of claim 213, further characterized by peaks at 12.75, 14.26 ± 0.2 degrees (2θ).   254. The crystal form of claim 214, further characterized by substantially the PXRD pattern of FIG.   The crystal form of claim 213, wherein the crystal form is fluvastatin sodium XLIII form. A process for the preparation of crystalline fluvastatin sodium Form XLIII comprising:
a) Dissolve fluvastatin sodium in water,
b) Propan-2-ol is added to induce XLIII type precipitation, and
c) Separate water and propan-2-ol from Form XLIII. A process for the preparation of crystalline fluvastatin sodium Form XLIII comprising:
a) Dissolve the lower alkyl ester of fluvastatin in an aqueous solution of NaOH,
b) Propan-2-ol is added to this solution to induce XLIII type precipitation, and
c) Separate the solution from XLIII.   3. Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.46, 4.05, 9.19, 10.14, 20.56 ± 0.2 degrees (2θ).   220. The crystal form of claim 219, further characterized by peaks at 6.26, 10.91, 11.12, 11.38, 15.98, 20.02, 22.21, 23.52, 25.45 ± 0.2 degrees (2θ).   The crystal form of claim 220, further characterized by a PXRD pattern substantially as in FIG.   220. The crystal form of claim 219, wherein the crystal form is fluvastatin sodium XLIV form. Process for the preparation of crystalline fluvastatin sodium XLIV form comprising:
a) producing a heterogeneous mixture of amorphous fluvastatin sodium and propan-2-ol;
b) maintaining the heterogeneous mixture at reflux temperature for a time sufficient to convert substantially amorphous sodium fluvastatin to Form XLIV, and
c) Recover XLIV from the mixture. Process for the preparation of crystalline fluvastatin sodium XLIV form comprising:
a) Dissolve fluvastatin free acid, lactone or a mixture thereof in acetone to form a solution,
b) Mix this solution with an ethanolic solution of sodium,
c) maintain the mixture for a time sufficient for fluvastatin sodium Form XLIV to precipitate; and
d) Separate XLIV from acetone and ethanol.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 5.1, 10.7, 17.8, and 20.3 ± 0.2 degrees (2θ).   The crystal form of claim 225, further characterized by peaks at 6.2, 14.5, 21.6, 22.6, and 25.2 ± 0.2 degrees (2θ).   The crystal form of claim 226, further characterized by substantially the PXRD pattern of FIG.   The crystal form of claim 225, wherein the crystal form is fluvastatin sodium XLV form. Method for the preparation of crystalline fluvastatin sodium form XLV comprising:
a) Amorphous fluvastatin sodium is suspended in propan-2-ol at room temperature to obtain XLV form, and
b) Separate propan-2-ol from form XLV.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.3, 3.5, 10.2, 11.2, and 21.1 ± 0.2 degrees (2θ).   235. The crystal form of claim 230, further characterized by peaks at 9.7, 12.1, 17.2, and 19.0 ± 0.2 degrees (2θ).   The crystal form of claim 231, wherein the crystal form is further characterized by a PXRD pattern substantially as in FIG.   230. The crystal form of claim 230, wherein the crystal form is fluvastatin sodium XLVI form. Process for the preparation of crystalline fluvastatin sodium XLVI type comprising:
a) contacting the lower alkyl ester of fluvastatin with about 1 molar equivalent of sodium in ethanol;
b) adding excess acetonitrile to ethanol,
c) precipitating XLVI form from a mixture of ethanol and acetonitrile, and
D) Separate ethanol and acetonitrile from XLVI.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.3, 10.2, and 18.0 ± 0.2 degrees (2θ).   235. The crystal form of claim 235, further characterized by peaks at 8.3, 10.8, 13.6, 20.7, and 21.3 ± 0.2 degrees (2θ).   242. The crystal form of claim 236, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   254. The crystal form of claim 235, wherein the crystal form is fluvastatin sodium XLVII. Process for the preparation of crystalline fluvastatin sodium form XLVII comprising:
a) contacting fluvastatin sodium form XVIII with water vapor in a container containing air of controlled high humidity compared to the air outside the container to convert form XV to form XII; and
b) Stop the humidity control in the container or remove the Model XV from the container.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.5, 6.7, 7.0, 10.9, 19.1, 21.7 ± 0.2 degrees (2θ).   243. The crystal form of claim 240, further characterized by peaks at 8.9, 12.9, 13.1, 13.5, 15.2, 16.8, 17.6, 18.3, 19.7, 20.6 ± 0.2 degrees (2θ).   The crystal form of claim 241, wherein the crystal form is further characterized by a PXRD pattern substantially as shown in FIG.   243. The crystal form of claim 240, wherein the crystal form is fluvastatin sodium XLVIII. Process for the preparation of crystalline fluvastatin sodium Form XLVIII comprising:
a) The lower alkyl ester of fluvastatin sodium is dissolved in a methanol solution of NaOH to hydrolyze the ester.
b) Add acetonitrile to this solution to induce precipitation of fluvastatin sodium, and
c) Separate fluvastatin sodium from methanol and acetonitrile. Process for the preparation of crystalline fluvastatin sodium Form XLVIII comprising:
a) Slurize fluvastatin sodium Form B in methanol at reflux temperature,
b) cooling the slurry,
c) stirring the slurry solution at room temperature,
d) Separate fluvastatin sodium from methanol as XLVIII form. Process for the preparation of crystalline fluvastatin sodium Form XLVIII comprising:
a) Dissolve fluvastatin sodium in methanol at room temperature,
b) heating the solution to reflux temperature to induce XLVIII type precipitation,
c) cooling the resulting slurry to room temperature,
d) stirring the slurry solution at room temperature, and
e) Separate XLVIII from methanol. Process for the preparation of crystalline fluvastatin sodium Form XLVIII comprising:
a) Dissolve fluvastatin in refluxing methanol,
b) Solid sodium hydroxide is added to this solution at reflux temperature to induce XLVIII type precipitation.
c) cooling the resulting slurry to ambient temperature,
d) stirring the slurry solution at room temperature, and
e) Separate XLVIII from methanol. Process for the preparation of crystalline fluvastatin sodium Form XLVIII comprising:
a) Dissolve fluvastatin in methanol at reflux temperature,
b) Solid sodium hydroxide is added to the resulting solution at reflux temperature to induce XLVIII type precipitation.
c) cooling the resulting slurry to ambient temperature,
d) adding acetone to the slurry, and
e) Separate XLVIII from methanol and acetone.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 5.0, 12.1, 13.5, and 20.2 ± 0.2 degrees (2θ).   254. The crystal form of claim 249, further characterized by peaks at 6.3, 10.1, and 17.1 ± 0.2 degrees (2θ).   265. The crystal form of claim 250, wherein the crystal form is further characterized by a PXRD pattern substantially as shown in FIG.   254. The crystal form of claim 249, wherein the crystal form is fluvastatin sodium XLIX. A process for the preparation of crystalline fluvastatin sodium XLIX form comprising:
a) heating a solution of fluvastatin sodium in methanol to high temperature,
b) adding methyl tert-butyl ether to methanol at high temperature to induce XLIX-type precipitation, and
c) Separate methanol and methyl tert-butyl ether from XLIX type.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 6.48, 6.92, 9.72, 12.64, 21.49 ± 0.2 degrees (2θ).   254. The crystal form of claim 254, further characterized by peaks at 4.53, 12.06, 13.50, 14.79, 15.79, 16.32, 19.15, 23.19 ± 0.2 degrees (2θ).   The crystal form of claim 255, further characterized by substantially the PXRD pattern of FIG.   254. The crystal form of claim 254, wherein the crystal form is fluvastatin sodium form L. Process for the preparation of crystalline fluvastatin sodium Form L comprising:
a) Dissolve fluvastatin sodium in methanol,
b) Add ethyl acetate to this solution at ambient temperature to induce L-form precipitation, and
c) Separate methanol and ethyl acetate from L-form.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 6.2, 10.8, 14.5, and 20.7 ± 0.2 degrees (2θ).   260. The crystal form of claim 259, further characterized by peaks at 8.9, 11.5, and 23.1 ± 0.2 degrees (2θ).   265. The crystal form of claim 260, further characterized by the PXRD pattern substantially as shown in FIG.   260. The crystal form of claim 259, wherein the crystal form is fluvastatin sodium LI form. Process for the preparation of crystalline fluvastatin sodium Form LI comprising:
a) heating a solution of fluvastatin sodium in methanol to high temperature,
b) adding acetonitrile to methanol at high temperature to induce LI-type precipitation, and
c) Separate methanol and acetonitrile from Form LI.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.6, 6.3, 10.5, 20.9 ± 0.2 degrees (2θ).   264. The crystal form of claim 264, further characterized by peaks at 14.3, 15.1, 15.6, and 17.1 ± 0.2 degrees (2θ).   276. The crystal form of claim 265, further characterized by the PXRD pattern substantially as shown in FIG.   264. The crystal form of claim 264, wherein the crystal form is fluvastatin sodium form LIII. Process for the preparation of crystalline fluvastatin sodium form LIII comprising:
a) heating a solution of fluvastatin sodium in methanol to high temperature,
b) adding ethyl acetate to methanol at high temperature to induce LIII type precipitation, and
c) Separate methanol and ethyl acetate from Form LIII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 10.4, 18.2, 19.6, 21.3 ± 0.2 degrees (2θ).   The crystal form of claim 269, wherein the crystal form is further characterized by peaks at 6.9, 12.1, 13.8, 17.7, 19.0 ± 0.2 degrees (2θ).   276. The crystal form of claim 270, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   The crystal form of claim 269, wherein the crystal form is fluvastatin sodium LIV form. Method for preparing crystalline fluvastatin sodium form LIV comprising:
a) contacting fluvastatin with aqueous sodium hydroxide for a time sufficient to form a suspension; and
b) Separate LIV form from water.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 5.0, 5.9, 12.2 ± 0.2 degrees (2θ).   278. The crystal form of claim 274, wherein the crystal form is further characterized by peaks at 5.6, 8.7, 10.1, 11.2 ± 0.2 degrees (2θ).   The crystal form of claim 275, wherein the crystal form further substantially comprises the PXRD pattern of FIG.   274. The crystal form of claim 274, wherein the crystal form is fluvastatin sodium LV form. A process for preparing crystalline fluvastatin sodium Form LV comprising:
a) Dissolve the lower alkyl ester of fluvastatin sodium in acetonitrile,
b) Add a solution of about 1 equivalent of sodium hydroxide in methanol,
c) precipitating fluvastatin sodium Form LV from the solution, and
d) Separate fluvastatin sodium Form LV from the solution.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 22.1, and 27.4 ± 0.2 degrees (2θ).   280. The crystal form of claim 279, further characterized by peaks at 6.8, 10.2, 13.6, 18.5, and 20.0 ± 0.2 degrees (2θ).   280. The crystal form of claim 280, further characterized by the PXRD pattern substantially as shown in FIG.   280. The crystal form of claim 279, wherein the crystal form is fluvastatin sodium LVI form. Process for the preparation of crystalline fluvastatin sodium Form LVI comprising:
a) cleaving the ketal group of a lower alkyl ester derivative of fluvastatin having ketal protecting groups on the β and δ hydroxyl groups in tetrahydrofuran under acidic conditions;
b) Add sodium hydroxide to neutralize the solution,
c) Distill off the tetrahydrofuran to leave a residue,
d) dissolving the residue in acetone,
e) Add about 1 molar equivalent of sodium hydroxide to acetone.
f) precipitating LVI form from acetone, and
g) Separate the acetone from the LVI form.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 5.0, 5.5, 10.1, 12.1 ± 0.2 degrees (2θ).   285. The crystal form of claim 284, wherein the crystal form is further characterized by peaks at 8.6, 11.1, 14.9, 21.7, 22.8 ± 0.2 degrees (2θ).   285. The crystal form of claim 285, further characterized by the PXRD pattern substantially as shown in FIG.   284. The crystal form of claim 284, wherein the crystal form is fluvastatin sodium form LVII. Process for the preparation of crystalline fluvastatin sodium Form LVII comprising:
a) producing a heterogeneous mixture of fluvastatin sodium type VII in ethanol;
b) maintaining a heterogeneous mixture to convert form VII to fluvastatin sodium form LVII, and
c) Separate form LVII from ethanol.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 3.8, 5.4, 5.7, 10.3 ± 0.2 degrees (2θ).   289. The crystal form of claim 289, wherein the crystal form is further characterized by peaks at 4.7, 7.2, 8.4, 11.5, 17.5, 20.4, 21.4, 23.1 ± 0.2 degrees (2θ).   308. The crystal form of claim 290, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   289. The crystal form of claim 289, wherein the crystal form is fluvastatin sodium form LVIII. Process for the preparation of crystalline fluvastatin sodium Form LVIII comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form B in propan-2-ol,
b) maintaining a heterogeneous mixture to convert form B to fluvastatin sodium form LVIII, and
c) Separate form LVIII from propan-2-ol.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 5.7, 10.8, 18.2, and 21.6 ± 0.2 degrees (2θ).   295. The crystal form of claim 294, further characterized by peaks at 12.4, 14.7, 20.4, 22.4, and 25.4 ± 0.2 degrees (2θ).   305. The crystal form of claim 295, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   295. The crystal form of claim 294, wherein the crystal form is fluvastatin sodium LXIX. Process for the preparation of crystalline fluvastatin sodium form LXIX comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form VI in propan-2-ol,
b) maintain the fluvastatin sodium heterogeneous mixture for a time sufficient to convert type VI to LXIX; and
c) Separate propan-2-ol from form LXIX.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.0, 3.4, 5.9, and 13.8 ± 0.2 degrees (2θ).   320. The crystal form of claim 299, further characterized by peaks at 8.2, 8.9, 18.6, 21.1, and 22.4 ± 0.2 degrees (2θ).   300. The crystal form of claim 300, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   302. The crystal form of claim 299, wherein the crystal form is fluvastatin sodium LXX form. Process for the preparation of crystalline fluvastatin sodium form LXX comprising:
a) dissolves in water at high temperature,
b) adding excess acetone to water to induce LXX-type precipitation, and
c) Separate water from acetone and LXX form.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.9, 7.8, 11.6, and 15.5 ± 0.2 degrees (2θ).   305. The crystal form of claim 304, further characterized by peaks at 9.2, 13.3, 19.0, and 23.2 ± 0.2 degrees (2θ).   305. The crystal form of claim 305, further characterized by the PXRD pattern substantially as shown in FIG.   305. The crystal form of claim 304, wherein the crystal form is fluvastatin sodium LXXI form. Method for preparing crystalline fluvastatin sodium form LXXI comprising:
a) Dissolve fluvastatin sodium in water at high temperature,
b) adding excess acetone to water to induce precipitation of type LXXI, and
c) Separate water and acetone from type LXXI.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 5.7, and 12.1 ± 0.2 degrees (2θ).   309. The crystal form of claim 309, further characterized by peaks at 5.0, 10.8, 16.8, and 20.1 ± 0.2 degrees (2θ).   340. The crystal form of claim 310, wherein the crystal form is further characterized by a PXRD pattern substantially as shown in FIG.   205. The crystal form of claim 205, wherein the crystal form is fluvastatin sodium form LXXII. A process for the preparation of crystalline fluvastatin sodium form LXXII comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form VI and a diluent selected from the group consisting of a mixture of acetonitrile and acetone and water;
b) maintaining the heterogeneous mixture at an elevated temperature for a time sufficient to convert type VI to type LXXII; and
c) Separate diluent from Form LXXII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.0, 12.8, 19.0, 19.9, and 25.8 ± 0.2 degrees (2θ).   335. The crystal form of claim 314, further characterized by peaks at 5.4, 11.8, 13.4, 18.0, and 24.6 ± 0.2 degrees (2θ).   316. The crystal form of claim 315, further characterized by the PXRD pattern substantially as shown in FIG.   335. The crystal form of claim 314, wherein the crystal form is fluvastatin sodium form LXXIV. Process for the preparation of crystalline fluvastatin sodium form LXXIV comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form B and a mixture of propan-2-ol and water;
b) maintain the mixture for a time sufficient to effect conversion to LXXIV form, and
c) Separate propan-2-ol and water from Form LXXIV.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.4, 6.6, 10.8, 14.3, and 22.2 ± 0.2 degrees (2θ).   320. The crystal form of claim 319, further characterized by peaks at 7.8, 15.0, 19.8, 20.4, and 21.4 ± 0.2 degrees (2θ).   335. The crystal form of claim 320, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   335. The crystal form of claim 320, wherein the crystal form is fluvastatin sodium LXXV form. Method for the preparation of crystalline fluvastatin sodium form LXXV comprising:
a) producing a heterogeneous mixture of fluvastatin sodium form XXX and methanol,
b) maintain the heterogeneous mixture for a time sufficient to convert form XXX to form LXV; and
c) Separate methanol from Form LXV.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.5, 7.0, 10.5, and 13.0 ± 0.2 degrees (2θ).   350. The crystal form of claim 324, further characterized by the PXRD pattern substantially as shown in FIG.   335. The crystal form of claim 324, wherein the crystal form is fluvastatin sodium form LXXVI. Method for preparing crystalline fluvastatin sodium form LXXVI comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with about 1 molar equivalent sodium base catalyst in a mixture of ethanol and water;
b) distilling off part of the mixture of ethanol and water,
c) add water to the remaining mixture,
d) extracting the mixture with a solvent that is not miscible with water;
e) Distill off ethanol and water to leave a residue of LXXVI type.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 8.8, 11.0, 12.8, and 17.8 ± 0.2 degrees (2θ).   338. The crystal form of claim 328, further characterized by peaks at 7.3, 20.2, and 31.0 ± 0.2 degrees (2θ).   345. The crystal form of claim 329, wherein the crystal form further substantially features the PXRD pattern of FIG.   335. The crystal form of claim 328, wherein the crystal form is fluvastatin sodium form LXXVII. Process for the preparation of fluvastatin sodium form LXXVII comprising:
a) Hydrolysis of fluvastatin sodium lower alkyl ester with a molar excess of sodium base catalyst in a mixture of water and ethyl acetate
b) precipitating LXXVII form from the mixture, and
c) Separate form LXXVII from water, ethyl acetate, and residual sodium base catalyst.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 8.8, 19.1, 27.2, 29.6, and 30.9 ± 0.2 degrees (2θ).   340. The crystal form of claim 333, further characterized by peaks at 3.4, 11.3, 17.7, 22.5, and 32.2 ± 0.2 degrees (2θ).   341. The crystal form of claim 334, wherein the crystal form is further characterized by substantially the PXRD pattern of FIG.   348. The crystal form of claim 333, wherein the crystal form is fluvastatin sodium form LXXVIII. A process for the preparation of crystalline fluvastatin sodium form LXXVIII comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium base catalyst in water,
b) bringing water into contact with an extraction solvent that does not mix with water,
c) Evaporate water to leave a residue,
d) contacting the residue with a liquid selected from the group consisting of propan-2-ol and acetonitrile to convert the residue to Form LXXVIII; and
e) Separate liquid from type LXXVIII.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.2 and 9.6 ± 0.2 degrees (2θ).   338. The semi-crystalline form of claim 338, further characterized by peaks at 11.8 and 19.8 ± 0.2 degrees (2θ).   40. The semi-crystalline form of claim 339, wherein the semi-crystalline form is further characterized by a PXRD pattern substantially as shown in FIG.   338. The semicrystalline form of claim 338, wherein the semicrystalline form is fluvastatin sodium form XC. Process for the preparation of semi-crystalline fluvastatin sodium form XC comprising:
a) Dissolve fluvastatin sodium in ethanol,
b) adding cyclohexane to ethanol to induce XC type precipitation, and
c) Separate ethanol and cyclohexane from form XC.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.7, 5.6, and 13.8 ± 0.2 degrees (2θ).   350. The fluvastatin sodium semi-crystalline form of claim 343 further characterized by peaks at 7.3, 9.6, 10.8, 16.4, 17.6, 19.8, 20.8, and 23.1 ± 0.2 degrees (2θ).   354. The semi-crystalline form of claim 344, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   352. The semi-crystalline form of claim 343, wherein the semi-crystalline form is fluvastatin sodium form XCI. Process for the preparation of semi-crystalline fluvastatin sodium form XCI comprising:
a) producing a heterogeneous mixture of Form XV and ethyl acetate,
b) maintain the mixture for a time sufficient to perform the conversion to XCI type, and
c) Separate ethyl acetate from Form XCI.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.4, 10.1, and 11.8 ± 0.2 degrees (2θ).   348. The semi-crystalline form of claim 348, further characterized by peaks at 4.1, 17.8, 20.1, 21.7, 23.4, and 25.3 ± 0.2 degrees (2θ).   352. The semi-crystalline form of claim 349, wherein the semi-crystalline form is further characterized by a PXRD pattern substantially as shown in FIG.   348. The semi-crystalline form of claim 348, wherein the semi-crystalline form is fluvastatin sodium form XCII. Process for the preparation of semicrystalline fluvastatin sodium form XCII comprising:
a) Dissolve fluvastatin sodium form B in ethanol: methanol mixture at high temperature,
b) Hexane is added to the mixture to induce precipitation of Form XCII fluvastatin sodium, and
c) Separate ethanol, methanol and hexane from Form XCII.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.6, 9.2, and 20.3 ± 0.2 degrees (2θ).   354. The semi-crystalline form of claim 353, further characterized by peaks at 4.1, 6.7, 13.0, 15.8, 17.7, 21.7, and 23.0 ± 0.2 degrees (2θ).   354. The semicrystalline form of claim 354, wherein the semicrystalline form is further characterized by substantially the PXRD pattern of FIG.   353. The semicrystalline form of claim 353, wherein the semicrystalline form is fluvastatin sodium form XCIV. Process for the preparation of semicrystalline fluvastatin sodium form XCIV comprising:
a) producing a heterogeneous mixture of fluvastatin sodium in butan-1-ol at ambient temperature;
b) maintaining the heterogeneous mixture at ambient temperature for a time sufficient to convert Form XV to Form XCIV; and
c) Separate butan-1-ol from Form XCIV.   A semicrystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.7, 13.0, 19.8, and 20.5 ± 0.2 degrees (2θ).   359. The semi-crystalline form of claim 358, further characterized by peaks at 4.2, 4.7, 12.3, and 15.9 ± 0.2 degrees (2θ).   356. The semi-crystalline form of claim 359, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   359. The semi-crystalline form of claim 358, wherein the semi-crystalline form is fluvastatin sodium XCV form. Method for preparing semi-crystalline fluvastatin sodium form XCV comprising:
a) producing a heterogeneous mixture of fluvastatin sodium form XV in a diluent selected from the group consisting of ethyl acetate, acetone, 1,4-dioxane, and MEK at ambient temperature;
b) maintaining the mixture at ambient temperature for a time sufficient to convert Form XV to Form XCV; and
c) Separate the diluent from the XCV type.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 11.0, 12.9, and 18.2 ± 0.2 degrees (2θ).   365. The semicrystalline form of claim 363, further characterized by peaks at 5.2, 8.3, 17.7, 21.5, and 25.5 ± 0.2 degrees (2θ).   437. The semi-crystalline form of claim 364, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   365. The semicrystalline form of claim 363, wherein the semicrystalline form is fluvastatin sodium form XCVI. Process for the preparation of semi-crystalline fluvastatin sodium form XCVI comprising:
a) producing a heterogeneous mixture of fluvastatin sodium form XV and THF at ambient temperature;
b) maintaining the suspension at ambient temperature for a time sufficient to convert form XV to form XCVI, and
c) THF is separated from Form XCV.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with a peak at 3.5 ± 0.2 degrees (2θ).   368. The semi-crystalline form of claim 368, further characterized by peaks at 9.4, 18.4, 20.0, 21.2, and 22.0 ± 0.2 degrees (2θ).   143. The semi-crystalline form of claim 369, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   368. The semicrystalline form of claim 368, wherein the semicrystalline form is fluvastatin sodium form XCVII. Process for the preparation of semicrystalline fluvastatin sodium form XCVII comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in cyclohexane,
b) precipitating form XCVII from cyclohexane, and
c) Separate cyclohexane from Form XCVII.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.8 and 10.8 ± 0.2 degrees (2θ).   437. The semicrystalline form of fluvastatin sodium of claim 373, further characterized by peaks at 6.4 and 14.4 ± 0.2 degrees (2θ).   375. The semi-crystalline form of claim 374, wherein the semi-crystalline form is further characterized by a PXRD pattern substantially as shown in FIG.   437. The semicrystalline form of claim 373, wherein the semicrystalline form is fluvastatin sodium form XCVIII. Process for the preparation of semi-crystalline fluvastatin sodium form XCVIII comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in concentrated methanol solution at high temperature,
b) adding excess acetonitrile to methanol at high temperature,
c) precipitating form XCVIII from methanol and acetonitrile, and
c) Separate methanol and acetonitrile from Form XCVIII.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 5.3, 8.7, and 10.4 ± 0.2 degrees (2θ).   379. The semi-crystalline form of claim 378, further characterized by peaks at 17.9 and 21.5 ± 0.2 degrees (2θ).   The semi-crystalline form of claim 379, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   379. The semicrystalline form of claim 378, wherein the semicrystalline form is fluvastatin sodium XCIX. Process for the preparation of semi-crystalline fluvastatin sodium form XCIX comprising:
a) producing a heterogeneous mixture of fluvastatin sodium Form VI and ethanol at ambient temperature;
b) maintaining the heterogeneous mixture at ambient temperature for a time sufficient to convert type VI to type XCIX; and
c) Separate ethanol from Form VI.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.3, 9.8, 11.0, 19.0, and 22.7 ± 0.2 degrees (2θ).   438. The semi-crystalline form of claim 383, further characterized by peaks at 6.2, 17.2, and 21.3 ± 0.2 degrees (2θ).   385. The semi-crystalline form of claim 384, further characterized by the PXRD pattern substantially as shown in FIG.   438. The semi-crystalline form of claim 383, wherein the semi-crystalline form is fluvastatin sodium form C. Process for the preparation of semi-crystalline fluvastatin sodium Form C comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in dichloromethane at room temperature,
b) precipitating fluvastatin sodium form C from dichloromethane, and
c) Separate dichloromethane from Form C.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.5 and 11.2 ± 0.2 degrees (2θ).   395. The semi-crystalline form of claim 388, further characterized by peaks at 5.7 and 19.3 ± 0.2 degrees (2θ).   138. The semi-crystalline form of claim 389, wherein the semi-crystalline form further features a PXRD pattern substantially as shown in FIG.   395. The semi-crystalline form of claim 388, wherein the semi-crystalline form is fluvastatin sodium CI type. Process for the preparation of semi-crystalline fluvastatin sodium Form CI comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in a mixture of acetone and methanol,
b) precipitating CI form from the mixture, and
c) Separate the mixture from CI type.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with a peak at 4.3 ± 0.2 degrees (2θ).   439. The semi-crystalline form of claim 393, further characterized by peaks at 8.7, 11.0, and 19.2 ± 0.2 degrees (2θ).   405. The semi-crystalline form of claim 394, wherein the semi-crystalline form is further characterized by a PXRD pattern substantially as shown in FIG.   439. The semicrystalline form of claim 393, wherein the semicrystalline form is fluvastatin sodium form CII. Process for the preparation of semi-crystalline fluvastatin sodium form CII comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in a mixture of acetone and methanol,
b) precipitating form CII from the mixture, and
c) Separate the mixture from Form CII.   A semicrystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.5, 20.4, 25.9, and 30.6 ± 0.2 degrees (2θ).   399. The semi-crystalline form of claim 398, further characterized by peaks at 5.6, 10.1, 12.5, 19.0, and 29.7 ± 0.2 degrees (2θ).   104. The semi-crystalline form of claim 399, further characterized by the PXRD pattern substantially as shown in FIG.   399. The semicrystalline form of claim 398, wherein the semicrystalline form is fluvastatin sodium form CIII. Process for the preparation of semi-crystalline fluvastatin sodium Form CIII comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in a mixture of acetone and water,
b) precipitating form CIII from the mixture, and
c) Separate the mixture from Form CIII.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 9.7, 18.3, 19.9, 21.8 ± 0.2 degrees (2θ).   405. The semi-crystalline form of claim 403, further characterized by peaks at 5.6, 11.3, 14.8, 22.6 ± 0.2 degrees (2θ).   405. The semi-crystalline form of claim 404, wherein the semi-crystalline form is further characterized by substantially the PXRD pattern of FIG.   405. The semi-crystalline form of claim 403, wherein the semi-crystalline form is fluvastatin sodium form CIV. Process for the preparation of semi-crystalline fluvastatin sodium Form CIV comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in THF,
b) Hexane is added to THF to induce CIV type precipitation, and
c) Separation of THF and hexane from Form CIV.   A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7, 8.9, 19.1, 22.5, 29.7 ± 0.2 degrees (2θ).   408. The semi-crystalline form of claim 408, further characterized by peaks at 11.5, 17.0, 25.1, 26.9, 28.2 ± 0.2 degrees (2θ).   408. The semi-crystalline form of claim 409, further characterized by the PXRD pattern substantially as shown in FIG.   408. The semicrystalline form of claim 408, wherein the semicrystalline form is fluvastatin sodium CV form. Process for the preparation of semi-crystalline fluvastatin sodium form CV comprising:
a) hydrolyzing the lower alkyl ester of fluvastatin with sodium hydroxide in acetonitrile at high temperature,
b) cooling acetonitrile,
c) precipitating form CV from acetonitrile, and
c) Separate acetonitrile from CV type.   I, II, III, IV, IV-1, V, VI, VII, VIII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, An effective amount of fluvastatin sodium selected from the group consisting of XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV type and mixtures thereof, and pharmaceutically acceptable And a pharmaceutical composition.   I, II, III, IV, IV-1, V, VI, VII, VIII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, An effective amount of fluvastatin sodium selected from the group consisting of XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV type and mixtures thereof, and pharmaceutically acceptable A pharmaceutical dosage form comprising:   I, II, III, IV, IV-1, V, VI, VII, VIII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, Administering to the patient an effective amount of fluvastatin sodium selected from the group consisting of XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV type and mixtures thereof. A method of treating a patient suffering from hypercholesterolemia or hyperlipidemia. A method of preparing fluvastatin sodium Form B comprising:
a) Dissolve fluvastatin free acid, lactone, or a mixture thereof in a mixture of methanol and water,
b) adding methyl tert-butyl ether to the solution to induce B-type precipitation; and
c) Separate methanol, water, and methyl tert-butyl ether from Form B. A method for preparing amorphous fluvastatin sodium comprising:
a) Dissolve fluvastatin sodium in 1,4-dioxane at high temperature,
b) cooling the solution to induce precipitation of amorphous fluvastatin sodium, and
c) Amorphous fluvastatin sodium is separated from 1,4-dioxane.   A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.7 and 4.4 ± 0.2 degrees (2θ).   418. The crystal form of claim 418, further characterized by peaks at 5.6 and 10.8 ± 0.2 degrees (2θ).   A method of preparing crystalline fluvastatin sodium form LXVII comprising combining a solution of a lower alkyl ester of fluvastatin in acetone with sodium hydroxide and methanol to precipitate the crystalline form.   Crystalline form of fluvastatin characterized by a PXRD pattern with peaks at 5, 6, 6.3, and 10.5 ± 0.2 degrees (2θ).   421. The crystal form of claim 421, further characterized by peaks at 4.1, 5.0, 11.0, 15.7, 17.2, and 19.6 ± 0.2 degrees (2θ).   A method of preparing fluvastatin sodium LX, comprising heating a solution of fluvastatin sodium in methanol and combining the solution with ethyl acetate to precipitate the crystalline form.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.8, 13.9, and 14.7 ± 0.2 degrees (2θ).   424. The crystal form of claim 424, further characterized by peaks at 5.1, 9.3, 11.7, and 19.4 ± 0.2 degrees (2θ).   A method for preparing crystalline fluvastatin LXIV, comprising precipitating the crystalline form from a mixture of acetone and methanol.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 5.8, 13.9, and 14.7 ± 0.2 degrees (2θ).   The crystal form of claim 427, further characterized by peaks at 5.1, 9.3, 11.7, and 19.4 ± 0.2 degrees (2θ).   A method for preparing fluvastatin sodium form LXV comprising adding propan-2-ol to a solution of fluvastatin sodium in methanol to precipitate the crystalline form.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 10.8, 17.8, 18.3, and 21.6 ± 0.2 degrees (2θ).   430. The crystal form of claim 430, further characterized by peaks at 7.2, 12.2, 14.4, and 25.5 ± 0.2 degrees (2θ).   A method for preparing crystalline fluvastatin sodium LXVI comprising heating a solution of fluvastatin sodium in water and cooling the solution to precipitate the crystalline form.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 3.6, 5.9, 10.8, and 11.6 ± 0.2 degrees (2θ).   435. The crystal form of claim 433, further characterized by peaks at 9.3, 15.4, 17.0, 18.4, and 23.0 ± 0.2 degrees (2θ).   A process for preparing crystalline fluvastatin sodium form LXVIII comprising combining a solution of a lower alkyl ester of fluvastatin in acetone with sodium hydroxide and methanol to precipitate the crystalline form. Process for the preparation of crystalline fluvastatin sodium Form II comprising:
a) heating solid fluvastatin sodium in a solvent selected from butan-1-ol and propan-2-ol;
b) crystallizing Form II from the solvent, and
c) Separate the solvent from Form II. Process for the preparation of crystalline fluvastatin sodium form III comprising:
a) heating fluvastatin sodium in a solvent selected from the group consisting of butan-1-ol, ethyl acetate, and THF;
b) slowly adding a poor solvent selected from the group consisting of MTBE, hexane, and cyclohexane to the solvent to precipitate type III; and
c) Separate solvent and anti-solvent from Form III. Process for the preparation of crystalline fluvastatin sodium form III comprising:
a) heating amorphous fluvastatin sodium in refluxing ethanol,
b) precipitating form III from ethanol, and
c) Separate ethanol from Form III. A method for preparing crystalline fluvastatin sodium Form V comprising:
a) Heat fluvastatin sodium in refluxing butan-1-ol,
b) Slowly add heptane to the refluxing solution,
c) precipitating form V from solution, and
d) Separate butan-1-ol and heptane from form V. A method for preparing crystalline fluvastatin sodium Form V comprising:
a) Fluvastatin sodium is heated at reflux temperature in a three solvent system of ethanol: ethyl acetate: propan-1-ol,
b) add n-hexane to the solution,
c) Precipitate Form V from solution and separate ethanol, ethyl acetate, propan-1-ol, and n-hexane from Form V. Process for the preparation of crystalline fluvastatin sodium Form IX-1 comprising:
a) heating fluvastatin sodium in a solvent selected from the group consisting of butan-1-ol, ethyl acetate, isobutyl acetate, ethanol, toluene, tetrahydrofuran, and methyl ethyl ketone;
b) adding a poor solvent selected from the group consisting of n-pentane, diethyl ether, methyl tert-butyl ether, dichloromethane, hexane, and cyclohexane to the solvent to induce precipitation of type IX-1; and
c) Separate solvent and anti-solvent from Form IX-1. Process for the preparation of crystalline fluvastatin sodium form XII comprising:
a) Heat fluvastatin sodium in butan-1-ol,
b) 1,4-dioxane is added to butan-1-ol to induce type XII precipitation; and
c) Separate 1,4-dioxane and butan-1-ol from Form XII.   Crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks at 4.9, 5.9, 7.2, and 12.3 ± 0.2 degrees (2θ).   443. The crystal form of claim 443, further characterized by peaks at 9.7, 10.9, and 13.9 ± 0.2 degrees (2θ).   A method for preparing fluvastatin sodium form XCIII comprising suspending fluvastatin sodium form XV in propan-1-ol to obtain form XCIII.

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